Hydrazonopyrazole derivatives and their use as therapeutics

ABSTRACT

Pharmaceutical compositions and compounds are provided. The compounds of the invention demonstrate anti-proliferative activity, and may promote apoptosis in cells lacking normal regulation of cell cycle and death. In one embodiment of the invention, pharmaceutical compositions of the compounds in combination with a physiologically acceptable carrier are provided. The pharmaceutical compositions are useful in the treatment of hyperproliferative disorders, which disorders include tumor growth, lymphoproliferative diseases, angiogenesis. The compounds of the invention are substituted pyrazoles and pyrazolines.

This application is a continuation application of U.S. patentapplication Ser. No. 10/497,046, filed Apr. 20, 2005 (now allowed),which is a national stage application filed under 35 U.S.C. 371 ofInternational Application No. PCT/CA02/01583, accorded an InternationalFiling Date of Oct. 18, 2002; which claims priority to U.S. ProvisionalPatent Application No. 60/335,265 filed Nov. 30, 2001 and to U.S. patentapplication Ser. No. 10/077,238 filed Feb. 15, 2002 (now U.S. Pat. No.7,105,503), which applications are incorporated herein in theirentireties.

FIELD OF INVENTION

It has become increasingly clear in recent years that cell death is asimportant to the health of a multicellular organism as cell division:where proliferation exists, so must a means of regulating its cellularprogeny. By repeated cell division and differentiation throughoutdevelopment or tissue repair, surplus or even harmful cells aregenerated, and they must be removed or killed. In adults, senescentcells are removed and replaced by newly generated cells to maintainhomeostasis.

The delicate interplay between growth and cell death in an organism ismirrored in the complex molecular balance that determines whether anindividual cell undergoes division; arrests in the cell cycle; orcommits to programmed cell death. Signal transduction is the termdescribing the process of conversion of extracellular signals, such ashormones, growth factors, neurotransmitters, cytokines, and others, to aspecific intracellular response such as gene expression, cell division,or apoptosis. This process begins at the cell membrane where an externalstimulus initiates a cascade of enzymatic reactions inside the cell thattypically include phosphorylation of proteins as mediators of downstreamprocesses which most often end in an event in the cell nucleus. Thechecks and balances of these signal transduction pathways can be thoughtof as overlapping networks of interacting molecules that control “go-nogo” control points. Since almost all known diseases exhibitdysfunctional aspects in these networks, there has been a great deal ofenthusiasm for research that provides targets and therapeutic agentsbased on signal transduction components linked to disease.

Dysregulation of cell proliferation, or a lack of appropriate celldeath, has wide ranging clinical implications. A number of diseasesassociated with such dysregulation involve hyperproliferation,inflammation, tissue remodelling and repair. Familiar indications inthis category include cancers, restenosis, neointimal hyperplasia,angiogenesis, endometriosis, lymphoproliferative disorders,graft-rejection, polyposis, loss of neural function in the case oftissue remodelling, and the like. Such cells may lose the normalregulatory control of cell division, and may also fail to undergoappropriate cell death.

In one example, epithelial cells, endothelial cells, muscle cells, andothers undergo apoptosis when they lose contact with extracellularmatrix, or bind through an inappropriate integrin. This phenomenon,which has been termed “anoikis” (the Greek word for “homelessness”),prevents shed epithelial cells from colonizing elsewhere, thusprotecting against neoplasia, endometriosis, and the like. It is also animportant mechanism in the initial cavitation step of embryonicdevelopment, in mammary gland involution, and has been exploited toprevent tumor angiogenesis. Epithelial cells may become resistant toanoikis through overactivation of integrin signaling. Anoikis resistancecan also arise from the loss of apoptotic signaling, for example, byoverexpression of Bcl-2 or inhibition of caspase activity.

An aspect of hyperproliferation that is often linked to tumor growth isangiogenesis. The growth of new blood vessels is essential for the laterstages of solid tumor growth. Angiogenesis is caused by the migrationand proliferation of the endothelial cells that form blood vessels.

In another example, a major group of systemic autoimmune diseases isassociated with abnormal lymphoproliferation, as a result of defects inthe termination of lymphocyte activation and growth. Often such diseasesare associated with inflammation, for example with rheumatoid arthritis,insulin dependent diabetes mellitus, multiple sclerosis, systemic lupuserythematosus, and the like. Recent progress has been made inunderstanding the causes and consequences of these abnormalities. At themolecular level, multiple defects may occur, which result in a failureto set up a functional apoptotic machinery.

The development of compounds that inhibit hyperproliferative diseases,particularly where undesirable cells are selectively targeted, is ofgreat medical and commercial interest.

Related Literature

The regulation of integrin linked kinase by phosphatidylinositol (3,4,5)trisphosphate is described by Delcommenne et al. (1998) Proc. Natl.Acad. Sci. 95:11211-6. Activated nitriles in heterocyclic synthesis arediscussed in Kandeel et al. (1985) J. Chem. Soc. Perkin. Trans. 1499.

SUMMARY OF THE INVENTION

Pharmaceutical compositions and compounds are provided. The compounds ofthe invention are substituted pyrazoles and pyrazolines. In oneembodiment of the invention, formulations of the compounds incombination with a physiologically acceptable carrier are provided. Thepharmaceutical compositions are useful in the treatment of disordersassociated with hyperproliferation and tissue remodelling or repair. Thecompounds are also active in the inhibition of specific protein kinases.

Accordingly, in one aspect, the invention provides pharmaceuticalcompositions which comprise a pharmaceutically acceptable carrier,diluent or excipient and a compound of formula (I):

wherein:

-   n is 0 to 5;-   R¹ and R² are each independently hydrogen, alkyl, aryl, aralkyl or    —C(O)R⁶;-   or R¹ and R² can each independently be a part of a double bond    within the pyrazole ring;-   R³ and R⁴ are each independently —N(R⁷)₂ or —N(R⁷)C(O)R⁶;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, nitro, cyano,    haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶,    —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH,    —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂,    —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂,    —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   or R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl,    heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1    to 4), —S(O)₂OH, —S(O)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶,    —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶,    —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl;-   as a single stereoisomer, a mixture of stereoisomers, a solvate or a    polymorph; or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier, diluent or excipientand a compound of formula (Ia):

wherein:

-   n is 0;-   R³ and R⁴ are each —NH₂; and-   R⁵ is phenyl substituted at the 4-position by fluoro and at the    3-position by trifluoromethyl, namely,    4-[(4-fluoro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine.

In another aspect, the invention provides methods of treating ahyperproliferative disorder in a mammal, wherein the method comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound of formula (I)as described above.

In another aspect, the invention provides compounds of formula (I):

wherein:

-   n is 0 to 5;-   R¹ and R² are each independently hydrogen, alkyl, aryl, aralkyl or    —C(O)R⁶;-   or R¹ and R² can each independently be a part of a double bond    within the pyrazole ring;-   R³ and R⁴ are each independently —N(R⁷)₂ or —N(R⁷)C(O)R⁶;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, nitro, cyano,    haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶,    —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH,    —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂,    —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂,    —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   or R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl,    heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1    to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶,    —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶,    —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl;-   provided that when n is 0, R¹ is phenyl, R² is hydrogen, R³ and R⁴    are both —NH₂, R⁵ can not be unsubstituted phenyl; and-   provided that when n is 0, R¹ and R² are both hydrogen, and R³ and    R⁴ are both —NH₂, R⁵ can not be phenyl, naphth-2-yl, pyridin-3-yl,    3-methoxyphenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl,    2-chlorophenyl, 3-nitrophenyl, 4-aminosulfonylphenyl, or    4-(pyrimidin-2-yl)aminosulfonylphenyl;-   as a single stereoisomer, a mixture of stereoisomers, a solvate or a    polymorph; or a pharmaceutically acceptable salt thereof.

In another aspect, this invention provides pharmaceutical compositionscomprising a pharmaceutically excipient and a compound of formula (Ic):

as a single tautomer, a mixture of tautomers, a single stereoisomer, amixture of stereoisomers, or a racemic mixture; or a pharmaceuticallyacceptable salt or solvate thereof; wherein:

-   R^(1c) is hydrogen, alkyl, aryl or aralkyl;-   R^(2c) is aryl (optionally substituted with one or more substituents    selected from the group consisting of halo, alkoxy, nitro,    haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   or R^(2c) is N-heterocyclyl (optionally substituted one or more    substituents selected from the group consisting of alkyl, halo, and    —C(O)OR^(7c));-   R^(4c) is hydrogen or alkyl;-   R^(3c) is hydrogen, alkyl, heterocyclylalkyl, or    heterocyclylcarbonyl;-   R^(5c) is hydrogen, alkyl, alkenyl, —R^(6c)—O—R^(12c),    —R^(6c)—S—R^(12c), —R^(6c)—N(R^(9c))₂, cycloalkyl (optionally    substituted by one or more substituents selected from the group    consisting of alkyl and aryl), aryl (optionally substituted by one    or more substituents selected from the group consisting of alkyl,    alkoxy, halo, haloalkyl, haloalkoxy, haloalkylthio, arylthioalkyl    (wherein the aryl group is optionally substituted with one or more    halo groups), nitro, —C(O)OR^(7c), and —N(R^(7c))—C(O)—R^(7c)),    aralkyl (wherein the aryl group is optionally substituted by one or    more substituents selected from the group consisting of alkyl,    alkoxy, halo, haloalkyl, haloalkoxy, haloalkylthio, arylthioalkyl    (wherein the aryl group is optionally substituted with one or more    halo groups), nitro, —C(O)OR^(7c), and —N(R^(7c))—C(O)—R^(7c)),    aralkenyl (wherein the aryl group is optionally substituted by one    or more halo groups), heterocyclyl (optionally substituted by one or    more substituents selected from the group consisting of alkyl, halo,    haloalkyl, alkyl thio, and aryl (optionally substituted with one or    more halo groups)), or heterocyclylalkyl;-   each R^(6c) is independently a straight or branched alkylene chain;-   each R^(7c) is independently hydrogen, alkyl, aryl, aralkyl or    heterocyclylakyl;-   R^(8c) is hydrogen, alkyl, aryl aralkyl or hydroxyalkyl;-   each R^(9c) is independently hydrogen, heterocyclylalkyl,    —C(O)—R^(11c), —C(O)—R^(10c)—C(O)OR^(7c), —R^(10c)—C(O)OR^(7c), or    —S(O)₂—R^(7c);-   each R^(10c) is independently a direct bond, straight or branched    alkylene chain or straight or branched alkenylene chain;-   R^(11c) is aryl (optionally substituted by one or more substituents    selected from the group consisting of alkyl and halo), heterocyclyl    (optionally substituted by one or more substituents selected from    the group consisting of —C(O)OR^(7c) and —C(O)N(R^(7c))₂) or    heterocyclylalkyl (optionally substituted by one or more    substituents selected from the group consisting of —C(O)OR^(7c) and    —C(O)N(R^(7c))₂); and-   each R^(12c) is independently aryl or aralkyl (optionally    substituted by one or more substituents selected from group    consisting of halo and nitro).

In another aspect, this invention is directed to certain compounds offormula (Ic) as described above.

In another aspect, this invention is directed to methods of using thecompounds of formula (Ic) as described above in the treatment ofdisorders associated with hyperproliferation and tissue remodelling orrepair. The compounds are also useful in the inhibition of specificprotein kinases.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions

In general, all technical and scientific terms used herein have the samemeaning as commonly understood to one of ordinary skill in the art towhich this invention belongs, unless clearly indicated otherwise. Forclarification, listed below are definitions for certain terms usedherein to describe the present invention. These definitions apply to theterms as they are used throughout this specification, unless otherwiseclearly indicated.

As used herein the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. For example, “acompound” refers to one or more of such compounds, while “the enzyme”includes a particular enzyme as well as other family members andequivalents thereof as known to those skilled in the art.

“Alkyl” refers to a straight or branched monovalent hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like. Unless stated otherwisespecifically in the specification, it is understood that for radicals,as defined below, that contain a substituted alkyl or alkenyl group thatthe substitution can occur on any carbon of the alkyl group.

“Alkylene chain” refers to a straight or branched divalent hydrocarbonchain consisting solely of carbon and hydrogen, containing nounsaturation and having from one to eight carbon atoms, e.g., methylene,ethylene, propylene, n-butylene, and the like.

“Alkenyl” refers to a straight or branched monovalent hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing atleast one double bond, having from two to eight carbon atoms, and whichis attached to the rest of the molecule by a single bond, e.g., ethenyl,prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above, e.g., methoxy, ethoxy, n-propoxy,1-methylethoxy(iso-propoxy), n-butoxy, n-pentoxy,1,1-dimethylethoxy(t-butoxy), and the like.

“Aryl” refers to a phenyl or naphthyl radical. Unless stated otherwisespecifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy, aryl,heterocyclyl, heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶(where m is 1 to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2),—S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶,—R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶ whereinR⁶, R⁷ and R are as defined herein.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isan alkyl radical as defined above and R_(b) is one or more aryl radicalsas defined above, e.g., benzyl, diphenylmethyl, and the like. The arylradical may be optionally substituted as described above.

“Aralkenyl” refers to a radical of the formula —R_(e)—R_(b) where R_(b)is an aryl radical as defined above and R_(e) is an alkenyl radical asdefined above, e.g., 2-phenylethenyl, and the like.

“Carboxy” refers to the —C(O)OH radical.

“Cycloalkyl” refers to a stable monovalent monocyclic or bicyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having from three to ten carbon atoms, and which is saturated andattached to the rest of the molecule by a single bond, e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and thelike. Unless otherwise stated specifically in the specification, theterm “cycloalkyl” is meant to include cycloalkyl radicals which areoptionally substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, halo, haloalkyl,haloalkoxy, hydroxy, amino, and carboxy.

“Halo” refers to bromo, chloro, iodo or fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Haloalkoxy” refers to a radical of the formula —OR_(c) where R_(c) isan haloalkyl radical as defined above, e.g., trifluoromethoxy,difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy,1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy,1-bromomethyl-2-bromoethoxy, and the like.

-   “Heterocyclyl” refers to a stable 3- to 15-membered ring radical    which consists of carbon atoms and from one to five heteroatoms    selected from the group consisting of nitrogen, oxygen and sulfur.    For purposes of this invention, the heterocyclyl radical may be a    monocyclic, bicyclic or tricyclic ring system, which may include    fused or bridged ring systems; and the nitrogen, carbon or sulfur    atoms in the heterocyclyl radical may be optionally oxidized; the    nitrogen atom may be optionally quaternized; and the heterocyclyl    radical may be aromatic or partially or fully saturated. The    heterocyclyl radical may not be attached to the rest of the molecule    at any heteroatom atom. Examples of such heterocyclyl radicals    include, but are not limited to, azepinyl, acridinyl,    benzimidazolyl, benzthiazolyl, benzothiadiazolyl, benzoxazolyl,    benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,    benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),    benzotriazolyl, carbazolyl, cinnolinyl, decahydroisoquinolyl,    dioxolanyl, furanyl, furanonyl, isothiazolyl, imidazolyl,    imidazolinyl, imidazolidinyl, isothiazolidinyl, indolyl, indazolyl,    isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl,    isoxazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl,    octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,    2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolyl,    oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl,    phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,    purinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,    pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,    quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl,    thiazolidinyl, thiadiazolyl, triazolyl, tetrazolyl, tetrahydrofuryl,    triazinyl, tetrahydropyranyl, thienyl, thiamorpholinyl,    thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. Unless    stated otherwise specifically in the specification, the term    “heterocyclyl” is meant to include heterocyclyl radicals as defined    above which are optionally substituted by one or more substituents    selected from the group consisting of alkyl, halo, nitro, cyano,    haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶,    —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH,    —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂,    —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂,    —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶ wherein R⁶, R⁷ and R⁸ and R⁹ are as    defined herein. Heterocyclyls that are preferred for R⁵ include    benzodioxolyl, benzodioxinyl, benzothiazolyl, triazolyl, pyrazolyl,    pyridinyl, carbazolyl, indazolyl, quinolinyl, isoquinolinyl,    benzotriazolyl, benzothiadiazolyl, quinazolinyl, benzothiophenyl    (benzothienyl), phthalazinyl, piperidinyl, morpholinyl, and    piperazinyl. Heterocyclyls that are preferred for substitutents on    the aryl choice for R⁵ include morpholinyl, piperidinyl,    pyrrolidinyl, piperidinyl and piperazinyl.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovewherein the one to five heteroatoms contained therein are selected onlyfrom nitrogen. Preferred N-heterocyclyl radicals for R² are thoseradicals selected from the group consisting of pyridinyl, thiazolyl,tetrazolyl, pyrazolyl, isoquinolinyl, quinolinyl, and phthalazinyl;

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)R_(d) whereR_(a) is an alkyl radical as defined above and R_(d) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. The heterocyclyl radical may beoptionally substituted as defined above. Preferred hetereocyclylradicals are defined above.

“Heterocyclylcarbonyl” refers to a radical of the formula —C(O)—R_(d)where R_(d) is a heterocyclyl radical as defined above, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl maybe attached to the carbonyl at the nitrogen atom. A preferredhetereocyclylcarbonyl radical for R³ is pyridinylcarbonyl.

As used herein, compounds which are “commercially available” may beobtained from standard commercial sources including Acros Organics(Pittsburgh Pa.), Aldrich Chemical (Milwaukee Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), AvocadoResearch (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester Pa.), Crescent ChemicalCo. (Hauppauge N.Y.), Eastman Organic Chemicals, Eastman Kodak Company(Rochester N.Y.), Fisher Scientific Co. (Pittsburgh Pa.), FisonsChemicals (Leicestershire UK), Frontier Scientific (Logan Utah), ICNBiomedicals, Inc. (Costa Mesa Calif.), Key Organics (Cornwall U.K.),Lancaster Synthesis (Windham N.H.), Maybridge Chemical Co. Ltd.(Cornwall U.K.), Parish Chemical Co. (Orem Utah), Pfaltz & Bauer, Inc.(Waterbury Conn.), Polyorganix (Houston Tex.), Pierce Chemical Co.(Rockford Ill.), Riedel de Haen AG (Hannover, Germany), Spectrum QualityProduct, Inc. (New Brunswick, N.J.), TCI America (Portland, Oreg.),Trans World Chemicals, Inc. (Rockville, Md.), and Wako Chemicals USA,Inc. (Richmond, Va.).

As used herein, “suitable conditions” for carrying out a synthetic stepare explicitly provided herein or may be discerned by reference topublications directed to methods used in synthetic organic chemistry.The reference books and treatise set forth above that detail thesynthesis of reactants useful in the preparation of compounds of thepresent invention, will also provide suitable conditions for carryingout a synthetic step according to the present invention.

As used herein, “methods known to one of ordinary skill in the art” maybe identified though various reference books and databases. Suitablereference books and treatise that detail the synthesis of reactantsuseful in the preparation of compounds of the present invention, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Specificand analogous reactants may also be identified through the indices ofknown chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., www.acs.org may be contacted formore details). Chemicals that are known but not commercially availablein catalogs may be prepared by custom chemical synthesis houses, wheremany of the standard chemical supply houses (e.g., those listed above)provide custom synthesis services.

“Prodrugs” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A. C. S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers which release the active compound of the invention in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and domesticated animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” and “salts thereof” in the compoundsof the present invention refers to pharmaceutically acceptable acidaddition salts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

“Pharmaceutically acceptable excipient” as used herein is intended toinclude without limitation any adjuvant, carrier, excipient, glidant,sweetening agent, diluent, preservative, dye/colorant, flavor enhancer,surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, emulsifier, or stabilizer which hasbeen approved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

“Treating” or “treatment” as used herein covers the treatment of ahyperproliferative disorder in a mammal, preferably a human, whichdisorder is characterized by integrin linked kinase (ILK) activity, andincludes:

-   -   (i) preventing the disorder from occurring in a mammal, in        particular a human, when such mammal is predisposed to the        disorder but has not yet been diagnosed as having it;    -   (ii) inhibiting the disorder, i.e., arresting its development;        or    -   (iii) relieving the disorder, i.e., causing regression of the        condition.

The nomenclature used herein is a modified form of the I.U.P.A.C.nomenclature system wherein the compounds of the invention are namedherein as derivatives of the pyrazole-3,5-diamine moiety if no otherfunctional group of higher nomenclature priority is present. Thus, acompound of formula (Ia) wherein n is 0, R¹ and R² are each hydrogen, R³and R⁴ are each —NH₂, and R⁵ is phenyl is named herein as4-(phenylhydrazono)-4H-pyrazole-3,5-diamine.

In compounds of formula (I), formula (Ia) and formula (Ib) the followingstructural moiety:

is used to represent a family of tautomeric structures. In part, theparticular tautomeric structure(s) encompassed by the compounds offormula (1), formula (Ia) and formula (Ib) depend on the selection of R³and R⁴. For example, when R³ and R⁴ are each —NH₂, and R¹ and R² areeach hydrogen or independently a part of a double bond, the followingtautomeric structures are possible for compounds of formula (I), formula(Ia) and formula (Ib):

Depending on the substitutions at R¹, R², R³ and R⁴ of formula (I), oneof ordinary skill in the art could easily ascertain which tautomericstructure would be available. All such tautomers are considered to bewithin the scope of the invention. Similar tautomeric structures arealso available for compounds of formula (Ia) and formula (Ib), as setforth above in the Summary of the Invention and herein, and are alsoconsidered to be within the scope of the invention.

Likewise, the following tautomeric structures are encompassed by thestructure depicted as formula (Ic):

Unless otherwise indicated by the nomenclature, compound names areintended to include any single tautomer, single stereoisomer,enantiomer, racemate or mixtures thereof.

B. Pharmaceutical Compositions and Administration

The compounds of this invention can be incorporated into a variety offormulations for therapeutic administration. More particularly, thecompounds of the present invention can be formulated into pharmaceuticalcompositions by combination with appropriate pharmaceutically acceptablecarriers or diluents, and may be formulated into preparations in solid,semi-solid, liquid or gaseous forms, such as tablets, capsules, powders,granules, ointments, solutions, suppositories, injections, inhalants,gels, microspheres, and aerosols. As such, administration of thecompounds can be achieved in various ways, including oral, buccal,rectal, parenteral, intraperitoneal, intradermal, transdermal,intracheal, etc., administration. The active agent may be systemic afteradministration or may be localized by the use of regionaladministration, intramural administration, or use of an implant thatacts to retain the active dose at the site of implantation.

In pharmaceutical dosage forms, the compounds may be administered in theform of their pharmaceutically acceptable salts. They may also be usedin appropriate association with other pharmaceutically active compounds.The following methods and excipients are merely exemplary and are in noway limiting.

For oral preparations, the compounds can be used alone or in combinationwith appropriate additives to make tablets, powders, granules orcapsules, for example, with conventional additives, such as lactose,mannitol, corn starch or potato starch; with binders, such ascrystalline cellulose, cellulose derivatives, acacia, corn starch orgelatins; with disintegrators, such as corn starch, potato starch orsodium carboxymethylcellulose; with lubricants, such as talc ormagnesium stearate; and if desired, with diluents, buffering agents,moistening agents, preservatives and flavoring agents.

The compounds can be formulated into preparations for injections bydissolving, suspending or emulsifying them in an aqueous or nonaqueoussolvent, such as vegetable or other similar oils, synthetic aliphaticacid glycerides, esters of higher aliphatic acids or propylene glycol;and if desired, with conventional additives such as solubilizers,isotonic agents, suspending agents, emulsifying agents, stabilizers andpreservatives.

The compounds can be utilized in aerosol formulation to be administeredvia inhalation. The compounds of the present invention can be formulatedinto pressurized acceptable propellants such as dichlorodifluoromethane,propane, nitrogen and the like.

Furthermore, the compounds can be made into suppositories by mixing witha variety of bases such as emulsifying bases or water-soluble bases. Thecompounds of the present invention can be administered rectally via asuppository. The suppository can include vehicles such as cocoa butter,carbowaxes and polyethylene glycols, which melt at body temperature, yetare solidified at ambient temperature.

Unit dosage forms for oral or rectal administration such as syrups,elixirs, and suspensions may be provided wherein each dosage unit, forexample, teaspoonful, tablespoonful, tablet or suppository, contains apredetermined amount of the composition containing one or more compoundsof the present invention. Similarly, unit dosage forms for injection orintravenous administration may comprise the compound of the presentinvention in a composition as a solution in sterile water, normal salineor another pharmaceutically acceptable carrier.

Implants for sustained release formulations are well known in the art.Implants are formulated as microspheres, slabs, etc. with biodegradableor non-biodegradable polymers. For example, polymers of lactic acidand/or glycolic acid form an erodible polymer that is well tolerated bythe host. The implant containing the inhibitory compounds is placed inproximity to the site of the tumor, so that the local concentration ofactive agent is increased relative to the rest of the body.

The term “unit dosage form”, as used herein, refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity of compounds ofthe present invention calculated in an amount sufficient to produce thedesired effect in association with a pharmaceutically acceptablediluent, carrier or vehicle. The specifications for the novel unitdosage forms of the present invention depend on the particular compoundemployed and the effect to be achieved, and the pharmacodynamicsassociated with each compound in the host.

The pharmaceutically acceptable excipients, such as vehicles, adjuvants,carriers or diluents, are readily available to the public. Moreover,pharmaceutically acceptable auxiliary substances, such as pH adjustingand buffering agents, tonicity adjusting agents, stabilizers, wettingagents and the like, are readily available to the public.

The combined use of the provided inhibitory compounds and othercytotoxic agents has the advantages that the required dosages for theindividual drugs is lower, and the effect of the different drugscomplementary. Depending on the patient and condition being treated andon the administration route, the subject inhibitory compounds may beadministered in dosages of 0.1 μg to 10 mg/kg body weight per day. Therange is broad, since in general the efficacy of a therapeutic effectfor different mammals varies widely with doses typically being 20, 30 oreven 40 times smaller (per unit body weight) in man than in the rat.Similarly the mode of administration can have a large effect on dosage.Thus for example oral dosages in the rat may be ten times the injectiondose. Higher doses may be used for localized routes of delivery.

A typical dosage may be a solution suitable for intravenousadministration; a tablet taken from two to six times daily, or onetime-release capsule or tablet taken once a day and containing aproportionally higher content of active ingredient, etc. Thetime-release effect may be obtained by capsule materials that dissolveat different pH values, by capsules that release slowly by osmoticpressure, or by any other known means of controlled release.

Those of skill will readily appreciate that dose levels can vary as afunction of the specific compound, the severity of the symptoms and thesusceptibility of the subject to side effects. Some of the specificcompounds are more potent than others. Preferred dosages for a givencompound are readily determinable by those of skill in the art by avariety of means. A preferred means is to measure the physiologicalpotency of a given compound.

For use in the subject methods, the subject compounds may be formulatedwith other pharmaceutically active agents, particularly otheranti-metastatic, anti-tumor or anti-angiogenic agents. Angiostaticcompounds of interest include angiostatin, endostatin, carboxy terminalpeptides of collagen alpha (XV), etc. Cytotoxic and cytostatic agents ofinterest include adriamycin, alkeran, Ara-C, BICNU, busulfan, CNNU,cisplatinum, cytoxan, daunorubicin, DTIC, 5-FU, hydrea, ifosfamide,methotrexate, mithramycin, mitomycin, mitoxantrone, nitrogen mustard,velban, vincristine, vinblastine, VP-16, carboplatinum, fludarabine,gemcitabine, idarubicin, irinotecan, leustatin, navelbine, taxol,taxotere, topotecan, etc.

C. Methods of Use

The compounds and pharmaceutical compositions of the invention areadministered to a subject having a hyperproliferative disorders, e.g. toinhibit tumor growth, to inhibit angiogenesis, to decrease inflammationassociated with a lymphoproliferative disorder, to inhibit graftrejection, or neurological damage due to tissue repair, etc. The presentcompounds are useful for prophylactic or therapeutic purposes. Theprevention of proliferation is accomplished by administration of thesubject compounds prior to development of overt disease, e.g. to preventthe regrowth of tumors, prevent metastatic growth, diminish restenosisassociated with cardiovascular surgery, etc. Alternatively the compoundsare used to treat ongoing disease, by stabilizing or improving theclinical symptoms of the patient.

The host, or patient, may be from any mammalian species, e.g. primatesp., particularly humans; rodents, including mice, rats and hamsters;rabbits; equines, bovines, canines, felines; etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the subjectcompounds may be determined by in vitro testing. Typically a culture ofthe cell is combined with a subject compound at varying concentrationsfor a period of time sufficient to allow the active agents to inducecell death or inhibit migration, usually between about one h and oneweek. For in vitro testing, cultured cells from a biopsy sample may beused. The viable cells left after treatment are then counted.

The dose will vary depending on the specific compound utilized, specificdisorder, patient status, etc. Typically a therapeutic dose will besufficient to substantially decrease the undesirable cell population inthe targeted tissue, while maintaining patient viability. Treatment willgenerally be continued until there is a substantial reduction, e.g. atleast about 50%, decrease in the cell burden, and may be continued untilthere are essentially none of the undesirable cells detected in thebody.

The compounds also find use in the specific inhibition of signalingpathway mediated by protein kinases. Protein kinases are involved insignaling pathways for such important cellular activities as responsesto extracellular signals and cell cycle checkpoints. Inhibition ofspecific protein kinases provides a means of intervening in thesesignaling pathways, for example to block the effect of an extracellularsignal, to release a cell from cell cycle checkpoint, etc. Defects inthe activity of protein kinases are associated with a variety ofpathological or clinical conditions, where there is a defect insignaling mediated by protein kinases. Such conditions include thoseassociated with defects in cell cycle regulation or in response toextracellular signals, e.g. hyperglycemia and diabetes Type I and TypeII, immunological disorders, e.g. autoimmune and immunodeficiencydiseases; hyperproliferative disorders, which may include psoriasis,arthritis, inflammation, angiogenesis, endometriosis, scarring, cancer,etc.

The compounds of the present invention are active in inhibiting purifiedkinase proteins, i.e. there is a decrease in the phosphorylation of aspecific substrate in the presence of the compound. A protein kinase ofparticular interest in integrin linked kinase (ILK). ILK is a serinethreonine kinase. The DNA and predicted amino acid sequence may beaccessed at Genbank, no. U40282, or as published in Hannigan et al.(1996) Nature 379:91-96. ILK regulates integrin extracellular activity(ECM interactions) from inside the cell via its direct interaction withthe integrin subunit. Interfering with ILK activity allows the specifictargeting of integrin function, while leaving other essential signalingpathways intact. Increased levels of cellular ILK activity shortcircuits the normal requirement for adhesion to extracellular membranein regulating cell growth. Thus, inhibiting ILK activity may inhibitanchorage-independent cell growth.

It is also known that many cell types undergo apoptosis if theappropriate contacts with extracellular matrix proteins are notmaintained (anoikis). The induction of apoptosis by the subjectcompounds in such cells predicts an association with the ILK signalingpathway.

The compounds of the present invention bind to protein kinases at a highaffinity, and find use as affinity reagents for the isolation and/orpurification of such kinases. Affinity chromatography is used as amethod of separating and purifying protein kinases and phosphatasesusing the biochemical affinity of the enzyme for inhibitors that act onit. The compounds are coupled to a matrix or gel. Preferably amicrosphere or matrix is used as the support. Such supports are known inthe art and commercially available. The inhibitor coupled support isused to separate an enzyme that binds to the inhibitor from a complexmixture, e.g. a cell lysate, that may optionally be partially purified.The sample mixture is contacted with the inhibitor coupled support underconditions that minimize non-specific binding. Methods known in the artinclude columns, gels, capillaries, etc. The unbound compounds arewashed free of the resin, and the bound proteins are then eluted in asuitable buffer.

The compounds of the invention may also be useful as reagents forstudying signal transduction or any of the clinical disorders listedthroughout this application.

Hyper-Proliferative Disorders of Interest

There are many disorders associated with a dysregulation of cellularproliferation. The conditions of interest include, but are not limitedto, the following conditions.

The subject methods are applied to the treatment of a variety ofconditions where there is proliferation and/or migration of smoothmuscle cells, and/or inflammatory cells into the intimal layer of avessel, resulting in restricted blood flow through that vessel, i.e.neointimal occlusive lesions. Occlusive vascular conditions of interestinclude atherosclerosis, graft coronary vascular disease aftertransplantation, vein graft stenosis, peri-anastomatic prosthetic graftstenosis, restenosis after angioplasty or stent placement, and the like.

Diseases where there is hyperproliferation and tissue remodelling orrepair of reproductive tissue, e.g. uterine, testicular and ovariancarcinomas, endometriosis, squamous and glandular epithelial carcinomasof the cervix, etc. are reduced in cell number by administration of thesubject compounds

Tumor cells are characterized by uncontrolled growth, invasion tosurrounding tissues, and metastatic spread to distant sites. Growth andexpansion requires an ability not only to proliferate, but also todown-modulate cell death (apoptosis) and activate angiogenesis toproduce a tumor neovasculature. Angiogenesis may be inhibited byaffecting the cellular ability to interact with the extracellularenvironment and to migrate, which is an integrin-specific function, orby regulating apoptosis of the endothelial cells. Integrins function incell-to-cell and cell-to-extracellular matrix (ECM) adhesiveinteractions and transduce signals from the ECM to the cell interior andvice versa. Since these properties implicate integrin involvement incell migration, invasion, intra- and extra-vasation, and plateletinteraction, a role for integrins in tumor growth and metastasis isobvious.

Tumors of interest for treatment include carcinomas, e.g. colon,duodenal, prostate, breast, melanoma, ductal, hepatic, pancreatic,renal, endometrial, stomach, dysplastic oral mucosa, polyposis, invasiveoral cancer, non-small cell lung carcinoma, transitional and squamouscell urinary carcinoma etc.; neurological malignancies, e.g.neuroblastoma, gliomas, etc.; hematological malignancies, e.g. childhoodacute leukaemia, non-Hodgkin's lymphomas, chronic lymphocytic leukaemia,malignant cutaneous T-cells, mycosis fungoides, non-MF cutaneous T-celllymphoma, lymphomatoid papulosis, T-cell rich cutaneous lymphoidhyperplasia, bullous pemphigoid, discoid lupus erythematosus, lichenplanus, etc.; and the like.

Some cancers of particular interest include breast cancers, which areprimarily adenocarcinoma subtypes. Ductal carcinoma in situ is the mostcommon type of noninvasive breast cancer. In DCIS, the malignant cellshave not metastasized through the walls of the ducts into the fattytissue of the breast. Infiltrating (or invasive) ductal carcinoma (IDC)has metastasized through the wall of the duct and invaded the fattytissue of the breast. Infiltrating (or invasive) lobular carcinoma (ILC)is similar to IDC, in that it has the potential metastasize elsewhere inthe body. About 10% to 15% of invasive breast cancers are invasivelobular carcinomas.

Also of interest is non-small cell lung carcinoma. Non-small cell lungcancer (NSCLC) is made up of three general subtypes of lung cancer.Epidermoid carcinoma (also called squamous cell carcinoma) usuallystarts in one of the larger bronchial tubes and grows relatively slowly.The size of these tumors can range from very small to quite large.Adenocarcinoma starts growing near the outside surface of the lung andmay vary in both size and growth rate. Some slowly growingadenocarcinomas are described as alveolar cell cancer. Large cellcarcinoma starts near the surface of the lung, grows rapidly, and thegrowth is usually fairly large when diagnosed. Other less common formsof lung cancer are carcinoid, cylindroma, mucoepidermoid, and malignantmesothelioma.

Melanoma is a malignant tumor of melanocytes. Although most melanomasarise in the skin, they also may arise from mucosal surfaces or at othersites to which neural crest cells migrate. Melanoma occurs predominantlyin adults, and more than half of the cases arise in apparently normalareas of the skin. Prognosis is affected by clinical and histologicalfactors and by anatomic location of the lesion. Thickness and/or levelof invasion of the melanoma, mitotic index, tumor infiltratinglymphocytes, and ulceration or bleeding at the primary site affect theprognosis. Clinical staging is based on whether the tumor has spread toregional lymph nodes or distant sites. For disease clinically confinedto the primary site, the greater the thickness and depth of localinvasion of the melanoma, the higher the chance of lymph node metastasesand the worse the prognosis. Melanoma can spread by local extension(through lymphatics) and/or by hematogenous routes to distant sites. Anyorgan may be involved by metastases, but lungs and liver are commonsites.

Other hyperproliferative diseases of interest relate to epidermalhyperproliferation, tissue remodelling and repair. For example, thechronic skin inflammation of psoriasis is associated with hyperplasticepidermal keratinocytes as well as infiltrating mononuclear cells,including CD4+ memory T cells, neutrophils and macrophages.

The proliferation of immune cells is associated with a number ofautoimmune and lymphoproliferative disorders. Diseases of interestinclude multiple sclerosis, rheumatoid arthritis and insulin dependentdiabetes mellitus. Evidence suggests that abnormalities in apoptosisplay a part in the pathogenesis of systemic lupus erythematosus (SLE).Other lymphoproliferative conditions the inherited disorder oflymphocyte apoptosis, which is an autoimmune lymphoproliferativesyndrome, as well as a number of leukemias and lymphomas. Symptoms ofallergies to environmental and food agents, as well as inflammatorybowel disease, may also be alleviated by the compounds of the invention.

Thus, in one aspect the present invention relates to therapeuticcompositions and methods for the treatment of inflammatory disordersincluding autoimmune diseases using compounds that inhibit ILK activity.Such disorders and diseases include, but are not limited to, psoriasis,rheumatoid arthritis, multiple sclerosis, scleroderma, systemic lupuserythematosus, Sjögren's syndrome, atopic dermatitis, asthma, andallergy. Target cells susceptible to the treatment include cellsinvolved in instigating autoimmune reactions as well as those sufferingor responding from the effects of autoimmune attack or inflammatoryevents.

Although psoriasis is not life threatening, the social stigma andreduction in quality of life associated with disease are profound issuesfor these patients and their families. Established anti-psoriasistherapies have been grouped into suppressive and remittive types.Suppressive therapies (e.g. cyclosporine, topical calcitriol,methotrexate, retinoids), produce plaque clearance although thesemedications are not associated with a complete normalization of skinpharmacodynamic markers or large reductions in plaque T cell numbers.Phototherapy with ultraviolet (UV) B (280-320 nm) light alone or incombination with coal tar derivatives and photochemotherapy with8-methoxypsoralen combined with UVA (320-400 nm) light (PUVA) areclassified as remittive-type anti-psoriasis therapies. UVB light andPUVA are typically delivered in multiple treatment sessions, oftenseveral times weekly, until plaque clearance is achieved. The presentinvention provides compounds that may be administered in combinationwith established anti-psoriasis therapies.

Renal Disorders of Interest

In one aspect of the invention, the compounds disclosed herein may beused to modulate integrin-linked kinase (ILK) for the treatment of renaldiseases. Thus, the present invention provides therapeutic compositionsand methods for treating renal disease, and specifically providestherapeutic compositions and methods directed to modulating, andespecially inhibiting, the activity of ILK so as to ameliorateglomerular renal disease states which may result in proteinuria, orstates characterized by tubular or tubulo-interstitial damage. Preferredcompounds of the invention may be identified by screening for biologicalactivity in an ILK-based functional assay, e.g. in vitro or in vivo ILKkinase activity.

According to current therapies, chronic progression of renal disease canbe slowed for 6-12 months using angiotensin-converting enzyme (ACE)inhibitors, but there is no other satisfactory treatment at this timebesides dialysis and ultimately transplantation of the organ. Accordingto the present invention, compounds of the invention serving as ILKinhibiting agents may be administered at an appropriate time, before,concurrent or after, in relation to a second therapy for treating renaldisorder, where that second therapy includes, but is not limited to,administration of an ACE inhibitor, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier to a mammal inneed thereof. ACE inhibitors include, but are not limited to, captopril,benazepril, enalapril, fosinopril, lisinopril, quinapril, ramipril,imidapril, perindopril, erbumine, and trandolapril. ACE ReceptorBlockers may also be used in place of, or as well as, ACE inhibitors,and these include losartan, irbesartan, candesartan, cilexetil, andvalsartan.

Thus, in one aspect, the present invention provides a method fortreating a patient with renal dysfunction comprising administering tothe patient an effective amount of a compound or pharmaceuticalcomposition of the invention. In various embodiments, the compound orcomposition is administered orally, or the compound is administeredintravenously, or the compound is administered intraperitneally. Thecompound may be administered intralumenally in or around the kidney. Thepatient may also be treated with an ACE inhibitor.

In one aspect, the present invention provides a method for lowering theprotein levels in urine, comprising administering to that patient aneffective amount of an compound or pharmaceutical composition of theinvention. In various embodiments, the compound or composition isadministered orally, or intravenously, or intraperitneally. The compoundmay be administered intralumenally in or around the kidney. The patientmay also be treated with an ACE inhibitor.

Eye Disorders

In one aspect, the present invention relates to the use of the compoundsand pharmaceutical compositions of the invention as disclosed herein asinhibitors of integrin-linked kinase (ILK) in the treatment of variouseye diseases with underlining pathology of neovascularization of cornea,iris, retina or choroids. The subject methods are used for prophylacticor therapeutic purposes to treat ocular diseases to prevent, reduce orreverse the loss of visual acuity as well as loss of vision secondary toneovascularization of cornea, iris, retina or choroid. While treatmentduring early stages is desirable, the adverse symptoms of the diseasemay be at least partially alleviated by treatment during later stages.

In one aspect, compounds of the invention that modulate the activity ofintegrin linked kinase (ILK) are administered systemically or locally totreat ophthalmic diseases with an underlining pathology that ischaracteristic of ocular neovascularization. Such a treatment is usedalone as single therapy or in combination with a second therapy as anadjunct to prevent, to reduce or to reverse the loss of visual acuity aswell as loss of vision secondary to neovascularization of cornea, iris,retina or choroids.

For example, in one aspect the invention is directed to a method toprevent, to reduce or to reverse ocular neovascularization in an eye ofan animal having a neovascular lesion, comprising the steps ofidentifying said lesion in the eye of the animal, administering to theanimal an amount of a compound of the invention as disclosed hereinsufficient to allow said compound to localize in said lesion. Methodsutilizing local administration that provides for a prolonged localizedconcentration, which may utilize sustained release implants, viscoussolutions, or other topical formulation, are of particular interest. Acompound of the invention may be administered alone as single therapy,or in combination with a second therapy, for example at an appropriatetime, before, concurrent or after, in relation to a second therapyincluding but not limited to Visudyne™ therapy, photocoagulation ortranspupillary thermotherapy as an adjunct treatment for ocularneovascularization.

Some examples of ocular disorders that may be treated by variousembodiments of the present invention include, without limitation:retinal diseases (diabetic retinopathy, chronic glaucoma, retinaldetachment, sickle cell retinopathy, age related macular degeneration(AMD) due to subretinal neovascularization); rubeosis iritis;inflammatory diseases; chronic uveitis; neoplasms (retinoblastoma,pseudoglioma); Fuchs' heterochromic iridocyclitis; neovascular glaucoma;corneal neovascularization (inflammatory, transplantation, developmentalhypoplasia of the iris); neovascularization resulting following acombined vitrectomy and lensectomy; vascular diseases (retinal ischemia,choroidal vascular insufficiency, choroidal thrombosis, carotid arteryischemia); neovascularization of the optic nerve; and neovascularizationdue to penetration of the eye or contusive ocular injury.

In practicing the method of treatment or use of a compound of theinvention in an ophthalmic diseases with an underlining pathology thatis characteristic of ocular neovascularization, a therapeuticallyeffective amount of a compound of the invention is administered to asubject afflicted with a disease or disorder related toneovascularization, or to a tissue that has been neovascularized. Thecompound may be administered in accordance with the method of theinvention either alone or in combination with other known therapies forneovascularization. When co-administered with one or more othertherapies, the compound may be administered either simultaneously withthe other treatment(s), or sequentially. If administered sequentially,the attending physician will decide on the appropriate sequence ofadministration, which may be before or after a second therapy.

Secondary therapies of interest include verteporfin (VISUDYNE™) therapy,see, for example Madreperla (2001) Arch Ophthalmol. 119(11):1606-1610;Harding (2001) Eye 15(Pt 3):407-12; Sharma (2001) Can Fam Physician47:955, 963; and photocoagulation or transpupillary thermotherapy, see,e.g., Rogers et al. (2001) Curr Opin Ophthalmol 12(3):212-5; Ardjomandet al. (2001) Ophthalmologica 215(3):241-4; Mainster et al. (2000)Ophthalmic Surg Lasers 31(5):359-73. Other therapies include, withoutlimitation, those set forth in U.S. Pat. No. 6,297,228, “Use ofangiostatic steroids in photodynamic therapy”, U.S. Pat. No. 6,271,233“Method for treating ocular neovascular diseases”; U.S. Pat. No.6,248,734 “Use of photodynamic therapy for prevention of secondarycataracts”; U.S. Pat. No. RE37,180 “Photochemotherapeutical obstructionof newly-formed blood vessels”; U.S. Pat. No. 6,225,303 “Use of greenporphyrins to treat neovasculature in the eye”; U.S. Pat. No. 6,217,895“Method for treating and/or preventing retinal diseases with sustainedrelease corticosteroids”; U.S. Pat. No. 6,214,819 “Method for treatingocular neovascular diseases”, and the like.

Some eye diseases lend themselves to acute treatment while othersrequire longer term therapy. Proliferative retinopathy can reach athreshold in a matter of days as seen in ROP, some cases of diabeticretinopathy, and neovascular glaucoma. Premature infants are at risk forneovascularization around what would be 35 weeks gestation, a few weeksafter birth, and will remain at risk for a short period of time untilthe retina becomes vascularized. Diabetic retinopathy can be acute butmay also smolder in the proliferative phase for considerably longer.Suitable animal models exist for determination of appropriate dosage,although the efficacy of a therapeutic effect for different mammalsvaries widely, for example doses typically are 20, 30 or even 40 timessmaller (per unit body weight) in man than in the rat. Similarly themode of administration can have a large effect on dosage. A murine modelof oxygen-induced retinal neovascularization has been established whichoccurs in 100% of treated animals and is quantifiable (Smith et al.(1994) Invest. Ophthalmol. Vis. Sci 35:101-111). Bioactivity can bedetermined by methods including the Miles vessel permeability assay(Miles and Miles (1952) J. Physiol. (Lond.) 118:228), which measuresvessel permeability, and endothelial cell mitogenicity, which measurescell growth.

For local application, a range of about 0.05 to 0.2 or about 0.5 mg/mlof a compound of the invention in an appropriate formulation isadministrated either intra-ocularly (intra-vitreous, subretinal,intra-anterior chamber, intra-scleral), peri-ocularly, or topically ontothe cornea. For systemic application, a range of 0.05 to 100 mg/kg bodyweight, preferably less than about 10 mg/kg is administered to treat eyedisease. For intra- or peri-ocular administration, a compound of theinvention in an injectable formulation is administered by either anintra-ocular injection at above-described concentrations and at afrequency of once every 2-6 months or by an intra-ocular implantation ofa device or a specific formulation of a compound of the inventionallowing sustained release of the ILK inhibitor over a period of time.For corneal application, a compound of the invention in an appropriateformulation is applied topically onto the cornea at a frequency of oncevery 4-6 hours. For systemic application, a compound of the invention inappropriate formulation is administered orally 1-3 times a day.

Thus, in one aspect, the present invention provides a method fortreating ocular neovascularization, the method comprising administeringa compound or pharmaceutical composition of the invention to treatocular neovascularization. Optionally, the treatment reduces or reversesthe loss of visual acuity secondary to neovascularization of cornea,iris, retina or choroid. The method may further comprise administering asecond therapy for ocular neovascularization, where a suitable secondtherapy is selected from the group consisting of Visudyne™ therapy,photocoagulation and transpupillary thermotherapy. In the presentmethod, the ocular neovascularization may be selected from the groupconsisting of diabetic retinopathy, chronic glaucoma, retinaldetachment, sickle cell retinopathy, age related macular degeneration(AMD) due to subretinal neovascularization; rubeosis iritis;inflammatory diseases; chronic uveitis; neoplasms; Fuchs' heterochromiciridocyclitis; neovascular glaucoma; corneal neovascularization;neovascularization resulting following a combined vitrectomy andlensectomy; retinal ischemia, choroidal vascular insufficiency,choroidal thrombosis, carotid artery ischemia; neovascularization of theoptic nerve; and neovascularization due to penetration of the eye orcontusive ocular injury. In various embodiments, the compound of theinvention is administered systemically, or intra-ocularly, orperi-ocularly, or is administered topically onto the cornea, or isadministered by intra-ocular injection, or is administered byintra-ocular implantation.

D. Preferred Embodiments

Of the pharmaceutical compositions described above in the Summary of theInvention, a preferred group is that group of pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, diluentor excipient and a compound of formula (I) wherein R¹ and R² are eachpart of a double bond of the pyrazole ring, i.e., a compound of formula(Ia):

Of this preferred group of pharmaceutical compositions, a preferredsubgroup is that subgroup of pharmaceutical compostions comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia) wherein:

-   n is 0 to 5;-   R³ and R⁴ are each independently —N(R⁷)₂ or —N(R⁷)C(O)R⁶;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, nitro, cyano,    haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶,    —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH,    —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂,    —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂,    —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subgroup of pharmaceutical compositions, a preferredclass is that class of pharmaceutical compositions comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, nitro, cyano,    haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶,    —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH,    —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂,    —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂,    —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred class of pharmaceutical compositions, a preferredsubclass is that subclass of pharmaceutical compositions comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl,    haloalkoxy, aryl, and aralkyl.-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass of pharmaceutical compositions, a preferredset of pharmaceutical compositions is that set comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl,    haloalkoxy, aryl and aralkyl; and-   each R⁷ is independently hydrogen or alkyl.

Of this preferred set of pharmaceutical compositions, a preferred subsetis that subset of pharmaceutical compositions comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia) wherein:

-   n is 0:-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl,    haloalkoxy, aryl, and aralkyl optionally substituted by —N(R⁷)₂; and-   each R⁷ is hydrogen or alkyl.

Of this preferred subset of pharmaceutical compositions, preferredpharmaceutical compositions are those comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound selected fromthe group consisting of the following:

-   4-[(4-fluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-ethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-chlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-fluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(3-phenylphenylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(2-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-iodophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(o-tolylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(2,6-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3,4-dichlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3,5-dichlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2-isopropylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2-chlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-iodophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(2,3,4,5,6-pentafluorophenylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(3,5-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,3,4-trifluorophenyl)hydrazono]4H-pyrazole-3,5-diamine;-   4-[(3-trifluoromethoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-chloro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-benzylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(4-(phenyl)phenylhydrazono)-4H-pyrazole-3,5-diamine;-   4-{[4-(4-methylaminobenzyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(2,3-difluoro-4-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-fluoro-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;    and-   N-ethyl-4-(phenylhydrazono)-4H-pyrazole-3,5-diamine.

Of the preferred subclass of pharmaceutical compositions set forthabove, another preferred set of pharmaceutical compositions is that setcomprising a pharmaceutically acceptable carrier, diluent or excipientand a compound of formula (Ia) wherein:

-   n is 0:-   R³ and R⁴ are each —NH₂; and-   R⁵ is naphthyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl, and    haloalkoxy.

Of this preferred set of pharmaceutical compositions, preferredpharmaceutical compositions are those comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound selected fromthe group consisting of the following:

-   4-(naphthalen-2-ylhydrazono)-4H-pyrazole-3,5-diamine; and-   4-[(4-bromonaphthalen-1-yl)hydrazono]-4H-pyrazole-3,5-diamine.

Of the preferred class of pharmaceutical compositions set forth above,another preferred subclass is that subclass of pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, diluentor excipient and a compound of formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of halo, haloalkyl, haloalkoxy,    —OR⁶, —R⁸—OR⁶, and —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4);-   each R⁶ is independently hydrogen, alkyl, aryl, or aralkyl;-   each R⁷ is independently hydrogen, alkyl, aryl, or aralkyl; and-   each R⁸ is a straight or branched alkylene chain.

Of this preferred subclass of pharmaceutical compositions, a preferredset is that set of pharmaceutical compositions comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —NH₂; and-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of halo, haloalkyl, haloalkoxy,    —OR⁶, —R⁸—OR⁶, and —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4);-   each R⁶ is independently hydrogen, alkyl, aryl, or aralkyl; and-   each R⁸ is a straight or branched alkylene chain.

Of this preferred set of pharmaceutical compositions, preferredpharmaceutical compositions are those comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound selected fromthe group consisting of the following:

-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenol;-   4-[(3-methoxyphenyl)hydrazono]4H-pyrazole-3,5-diamine;-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-phenoxy-phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-phenoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-chloro-4-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3,4-dimethoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-methoxy-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   {2-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol;-   {2-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol; and-   4-({3-[2-(2-methoxyethoxy)ethoxymethyl]phenyl}hydrazono)-4H-pyrazole-3,5-diamine.

Of the preferred class of pharmaceutical compositions set forth above,another preferred subclass is that subclass of pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, diluentor excipient and a compound of formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, nitro, —OR⁶, —R⁸—OR⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass of pharmaceutical compositions, a preferredset is that set of pharmaceutical compositions comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —NH₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, nitro, —OR⁶, —R⁸—OR⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, or aralkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    —R⁸—OR⁹, or heterocyclyl optionally substituted by —C(O)N(R⁹)₂;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred set of pharmaceutical compositions, preferredpharmaceutical compositions are those comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound selected fromthe group consisting of the following:

-   5-{4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzylamino}-[2,1,3]-thiadiazole-4-carboxylic    acid amide;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzoic acid ethyl    ester;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzoic acid ethyl    ester;-   4-[(3-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methoxy-3-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-nitro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-phenylaminophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-diethylaminomethylphenol;-   4-[(2-methyl-5-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   {3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-5-nitrophenyl}methanol;-   4-[(3-diethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;    and-   4-[(3-dimethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine.

Of the preferred class of pharmaceutical compositions set forth above,another preferred subclass is that subclass of pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, diluentor excipient and a compound of formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of —S(O)₂OH, —S(O)_(t)R⁷ (where t    is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂, and —R⁸—P(O)(OR⁹)₂,-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass of pharmaceutical compositions, preferredpharmaceutical compositions are those comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound selected fromthe group consisting of the following:

-   4-[(4-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2-benzenesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2,6-dimethylpyrimidin-4-yl)benzenesulfonamide;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   4-[(3-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(pyrimidin-2-yl)benzenesulfonamide;-   1-{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}ethanethione;-   {4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzyl}phosphonic    acid diethyl ester;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   4-[(4-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   N-butyl-3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   4-[(3-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[4-(morpholine-4-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-{[4-(pyrrolidine-1-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(3-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   2-{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanol;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamide;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamide;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamide;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamide;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2-hydroxyethyl)benzenesulfonamide;-   3-[N′-(3-amino-5-dimethylaminopyrazol-4-ylidene)-hydrazino]-N-methyl-benzenesulfonamide;    and-   3-[N′-(3-amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide.

Of the preferred class of pharmaceutical compositions set forth above,another preferred subclass is that subclass of pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, diluentor excipient and a compound of formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, nitro, halo, haloalkyl,    haloalkoxy, heterocyclyl, heterocyclylalkyl (optionally substituted    by alkyl), and —OR⁶;-   R⁶ is hydrogen or alkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass, a preferred set is that set ofpharmaceutical compositions comprising a pharmaceutically acceptablecarrier, diluent or excipient and a compound of formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, nitro, halo, haloalkyl,    haloalkoxy, morpholinyl, piperidinyl, morpholinylmethyl,    morpholinylethyl, pyrrolidinylmethyl, piperidinylmethyl, and    piperazinylmethyl (optionally substituted by alkyl), and —OR⁶; and-   R⁶ is hydrogen or alkyl; and-   each R⁷ is independently hydrogen or alkyl.

Of this preferred set of pharmaceutical compositions, preferredpharmaceutical compositions are those comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound selected fromthe group consisting of the following:

-   4-[(4-morpholin-4-ylphenyl)hydrazono]4H-pyrazole-3,5-diamine;-   4-[(3-chloro-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-(piperidin-1yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methyl-3-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methoxy-3-(morpholin-4-yl)methylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-(morpholin-4-yl)methylphenol;-   4-[(2-methyl-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-fluoro-2-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-(morpholin-4-ylmethyl)-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-fluoro-4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[4-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-{[3-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(3-(morpholin-4-ylmethyl)-5-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[4-(2-(morpholin-4-yl)ethyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(3-(pyrrolidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-fluoro-phenyl)-hydrazono]-N,N-dimethyl-4H-pyrazole-3,5-diamine;-   {3-[N′-(3-amino-5-dimethylaminopyrazol-4-ylidene)-hydrazino]-5-trifluoromethylphenyl}-methano;    and-   N,N-dimethyl-4-[(3-morpholin-4-ylmethylphenyl)-hydrazono]-4H-pyrazole-3,5-diamine.

Of the preferred subgroup of pharmaceutical compositions set forthabove, another preferred class is that class of pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, diluentor excipient and a compound of formula (Ia) wherein:

-   n is 0 to 5;-   R³ and R⁴ are each independently —N(R⁷)₂ or —N(R⁷)C(O)R⁶;-   R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl,    heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1    to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶,    —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶,    —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred class of pharmaceutical compositions, a preferredsubclass is that subclass of pharmaceutical compositions comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each independently —N(R⁷)₂;-   R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    haloalkyl, heterocyclyl, heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, and    —N(R⁷)₂-   R⁶ is alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass of pharmaceutical compositions, a preferredset is that set of pharmaceutical compositions comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia) wherein:

-   n is 0;-   R³ and R⁴ are each independently —N(R⁷)₂;-   R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    haloalkyl, —OR⁶, —R⁸—OR⁶, and —N(R⁷)₂, morpholinyl, piperidinyl,    piperazinyl (optionally substituted by alkyl);-   R⁶ is hydrogen, alkyl, aryl, or aralkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred set of pharmaceutical compositions, preferredpharmaceutical compositions are those comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound of formula (Ia)selected from the group consisting of the following:

-   4-(benzo[1,3]dioxol-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(5-methoxybenzothiazol-2-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(benzothiazol-2-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(4H-[1,2,4]-triazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(1H-pyrazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(pyridin-4-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(pyridin-3-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(9-ethyl-9H-carbazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(6-methoxypyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(1H-indazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(quinolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(6-chloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(isoquinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(quinolin-3-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(benzo[1,2,5]thiadiazol-4-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(quinolin-8-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(quinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2-methyl-2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(benzo[2,1,3]thiadiazol-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   7-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-4-trifluoromethylchroman-2-one;-   4-(quinazolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(1-methyl-1H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-methyl-3H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,2-difluorobenzo[1,3]dioxol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(1,1-dioxo-1H-benzo[b]thiophen-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(phthalazin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(6-(piperidin-1-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(6-(morpholin-4-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[6-(4-methylpiperazin-1-yl)pyridin-3-yl]hydrazono}-4H-pyrazole-3,5-diamine;-   2-[{5-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]pyridin-2-yl}(2-hydroxyethyl)amino]ethanol;-   4-[(2,6-dimethoxypyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,6-dichloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(6-fluoropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methylpyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   N,N-dimethyl-4-(quinolin-6-yl-hydrazono)-4H-pyrazole-3,5-diamine;-   4-[(6-chloro-pyridin-3-yl)-hydrazono]-N,N-dimethyl-4H-pyrazole-3,5-diamine;-   4-[(6-fluoro-pyridin-3-yl-hydrazono]-N,N-dimethyl-4H-pyrazole-3,5-diamine;-   N,N-dimethyl-4-(phthalazin-5-yl-hydrazono)-4H-pyrazole-3,5-diamine;    and-   N,N-dimethyl-4-(pyridin-3-yl-hydrazono)-4H-pyrazole-3,5-diamine.

Of the pharmaceutical compositions described above in the Summary of theInvention, another preferred group is that group of pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, diluentor excipient and a compound of formula (I) having the following formula(Ib):

wherein:

-   n is 0 to 5;-   R¹ is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁶;-   R³ and R⁴ are each independently —N(R⁷)₂ or —N(R⁷)C(O)R⁶;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, nitro, cyano,    haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶,    —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH,    —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂,    —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂,    —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   or R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl,    heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1    to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶,    —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶,    —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred group of pharmaceutical compositions, a preferredsubgroup is that subgroup of pharmaceutical compositions comprising apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ib) wherein:

-   n is 0;-   R¹ is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁶;-   R³ and R⁴ are each independently —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl,    haloalkoxy, or aryl;-   or R⁵ is pyridinyl;-   R⁶ is alkyl, aryl, or aralkyl; and-   each R⁷ is independently hydrogen or alkyl.

Of this preferred subgroup of pharmaceutical compositions, preferredpharmaceutical compositions are those comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound of formula (Ib)selected from group consisting of the following:

-   1-phenyl-4-phenylazo-1H-pyrazole-3,5-diamine;-   (3,5-diamino-4-phenylazopyrazol-1-yl)phenylmethanone;-   1-(4-bromophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine;-   4-(3,5-diamino-4-phenylazopyrazol-1-yl)benzoic acid;-   1-(4-fluorophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine;-   1-methyl-4-phenylazo-1H-pyrazole-3,5-diamine;-   1-benzyl-4-phenylazo-1H-pyrazole-3,5-diamine;-   1-{2-[3,5-diamino-4-(pyridin-3-ylazo)pyrazol-1-yl]-2-oxoethyl}pyrrolidine-2-carboxylic    acid methyl ester; and-   4-(isoquinolin-5-ylazo)-1-methyl-1H-pyrazole-3,5-diamine.

Of the pharmaceutical compositions set forth above in the Summary of theInvention, a preferred pharmaceutical composition comprises apharmaceutically acceptable carrier, diluent or excipient and a compoundof formula (Ia):

wherein:

-   n is 0;-   R³ and R⁴ are each —NH₂; and-   R⁵ is phenyl substituted at the 4-position by fluoro and at the    3-position by trifluoromethyl, namely,    4-[(4-fluoro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine.

Of the methods of treating a hyperproliferative disorder in a mammal asset forth above in the Summary of the Invention, a preferred method isthat method wherein the mammal is a human. Of this preferred method,preferred hyperproliferative disorders include the growth of solid tumorcarcinoma cells, angiogenesis, neointimal hyperplasia,lymphoproliferative disorder, cellular migration. Preferably thepreferred method comprises administering to a human in need thereof atherapeutically effective amount of a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, diluent or excipienand the compound,4-[(4-fluoro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine.

Of the compounds of formula (I) as set forth above in the Summary of theInvention, a preferred group is that group of compounds of formula (Ia):

Of this preferred group of compounds, a preferred subgroup is thatsubgroup of compounds wherein:

-   n is 0 to 5;-   R³ and R⁴ are each independently —N(R⁷)₂ or —N(R⁷)C(O)R⁶;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, nitro, cyano,    haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶,    —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH,    —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂,    —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂,    —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subgroup, a preferred class is that class of compoundswherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, nitro, cyano,    haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶,    —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH,    —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂,    —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂,    —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred class of compounds, a preferred subclass is thatsubclass of compounds wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl,    haloalkoxy, aryl, and aralkyl.-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass of compound, a preferred set is that set ofcompounds wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl,    haloalkoxy, aryl and aralkyl; and-   each R⁷ is independently hydrogen or alkyl.

Of this preferred set of compounds, a preferred subset is that subset ofcompounds wherein:

-   n is 0:-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl,    haloalkoxy, aryl, and aralkyl optionally substituted by —N(R⁷)₂; and-   each R⁷ is hydrogen or alkyl.

Of this preferred subset of compounds, preferred compounds are selectedfrom the group consisting of the following:

-   4-[(4-fluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-ethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-fluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(3-phenylphenylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(2-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-iodophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,6-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3,4-dichlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3,5-dichlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2-isopropylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-iodophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(2,3,4,5,6-pentafluorophenylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(3,5-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,3,4-trifluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-trifluoromethoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-chloro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-benzylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(4-(phenyl)phenylhydrazono)-4H-pyrazole-3,5-diamine;-   4-{[4-(4-methylaminobenzyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(2,3-difluoro-4-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-fluoro-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;    and-   N-ethyl-4-(phenylhydrazono)-4H-pyrazole-3,5-diamine.

Of the preferred subclass of compounds set forth above, anotherpreferred set of compounds is that set of compounds wherein:

-   n is 0:-   R³ and R⁴ are each —NH₂; and-   R⁵ is naphthyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl, and    haloalkoxy.

Of this preferred set of compounds, a preferred compound is4-[(4-bromonaphthalen-1-yl)hydrazono]-4H-pyrazole-3,5-diamine.

Of the preferred class of compounds set forth above, another preferredsubclass is that subclass of compounds wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of halo, haloalkyl, haloalkoxy,    —OR⁶, —R⁸—OR⁶, and —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4);-   each R⁶ is independently hydrogen, alkyl, aryl, or aralkyl;-   each R⁷ is independently hydrogen, alkyl, aryl, or aralkyl; and-   each R⁸ is a straight or branched alkylene chain.

Of this preferred subclass of compounds, a preferred set is that set ofcompounds wherein:

-   n is 0;-   R³ and R⁴ are each —NH₂; and-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of halo, haloalkyl, haloalkoxy,    —OR⁶, —R⁸—OR⁶, and —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4);-   each R⁶ is independently hydrogen, alkyl, aryl, or aralkyl; and-   each R⁸ is a straight or branched alkylene chain.

Of this preferred set of compounds, preferred compounds are selectedfrom the group consisting of the following:

-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenol;-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-phenoxy-phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-phenoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-chloro-4-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3,4-dimethoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-methoxy-5-trifuoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   {2-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol;-   {2-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol; and-   4-({3-[2-(2-methoxyethoxy)ethoxymethyl]phenyl}hydrazono)-4H-pyrazole-3,5-diamine.

Of the preferred class of compounds set forth above, another preferredsubclass is that subclass of compounds wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, nitro, —OR⁶, —R⁸—OR⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass of compounds, a preferred set is that set ofcompounds wherein:

-   n is 0;-   R³ and R⁴ are each —NH₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, nitro, —OR⁶, —R⁸—OR⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, or aralkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    —R⁸—OR⁹, or heterocyclyl optionally substituted by —C(O)N(R⁹)₂;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred set of compounds, preferred compounds are selectedfrom the group consisting of the following:

-   5-{4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzylamino}-[2,1,3]-thiadiazole-4-carboxylic    acid amide;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzoic acid ethyl    ester;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzoic acid ethyl    ester;-   4-[(4-methoxy-3-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-nitro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-phenylaminophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-diethylaminomethylphenol;-   4-[(2-methyl-5-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   {3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-5-nitrophenyl}methanol;-   4-[(3-diethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;    and-   4-[(3-dimethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine.

Of the preferred class of compounds set forth above, another preferredsubclass is that subclass of compounds wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of —S(O)₂OH, —S(O)_(t)R⁷ (where t    is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂, and —R⁸—P(O)(OR⁹)₂,-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass of compounds, preferred compounds areselected from the group consisting of the following:

-   4-[(4-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2-benzenesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2,6-dimethylpyrimidin-4-yl)benzenesulfonamide;-   4-[(3-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   1-{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}ethanethione;-   {4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzyl}phosphonic    acid diethyl ester;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   4-[(4-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   N-butyl-3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   4-[(3-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[4-(morpholine-4-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-{[4-(pyrrolidine-1-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(3-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   2-{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanol;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamide;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamide;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamide;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamide;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2-hydroxyethyl)benzenesulfonamide;-   3-[N′-(3-amino-5-dimethylaminopyrazol-4-ylidene)-hydrazino]-N-methyl-benzenesulfonamide;    and-   3-[N′-(3-amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide.

Of the preferred class of compounds set forth above, another preferredsubclass is that subclass of compounds wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, nitro, halo, haloalkyl,    haloalkoxy, heterocyclyl, heterocyclylalkyl (optionally substituted    by alkyl), and —OR⁶;-   R⁶ is hydrogen or alkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl,-   heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass of compounds, a preferred set is that set ofcompounds wherein:

-   n is 0;-   R³ and R⁴ are each —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, nitro, halo, haloalkyl,    haloalkoxy, morpholinyl, piperidinyl, morpholinylmethyl,    morpholinylethyl, pyrrolidinylmethyl, piperidinylmethyl, and    piperazinylmethyl (optionally substituted by alkyl), and —OR⁶; and-   R⁶ is hydrogen or alkyl; and-   each R⁷ is independently hydrogen or alkyl.

Of this preferred set of compounds, preferred compounds are selectedfrom the group consisting of the following:

-   4-[(4-morpholin-4-ylphenyl)hydrazono]4H-pyrazole-3,5-diamine;-   4-[(3-chloro-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-(piperidin-1yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methyl-3-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methoxy-3-(morpholin-4-yl)methylphenyl)hydrazono]4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-(morpholin-4-yl)methylphenol;-   4-[(2-methyl-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-fluoro-2-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-(morpholin-4-ylmethyl)-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-fluoro-4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[4-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-{[3-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(3-(morpholin-4-ylmethyl    5-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[4-(2-(morpholin-4-yl)ethyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(3-(pyrrolidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-fluoro-phenyl)-hydrazono]-N,N-dimethyl-4H-pyrazole-3,5-diamine;-   {3-[1′-(3-amino-5-dimethylaminopyrazol-4-ylidene)-hydrazino]-5-trifluoromethylphenyl}methano;    and-   N,N-dimethyl-4-[(3-morpholin-4-ylmethylphenyl)-hydrazono]-4H-pyrazole-3,5-diamine.

Of the preferred subgroup of compounds set forth above, anotherpreferred class is that class of compounds wherein:

-   n is 0 to 5;-   R³ and R⁴ are each independently —N(R⁷)₂ or —N(R⁷)C(O)R⁶;-   R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl,    heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to    4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶,    —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶,    —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred class of compounds, a preferred subclass is thatsubclass of compounds wherein:

-   n is 0;-   R³ and R⁴ are each independently —N(R⁷)₂;-   R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    haloalkyl, heterocyclyl, heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, and    —N(R⁷)₂-   R⁶ is alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subclass of compounds, a preferred set is that set ofcompounds wherein:

-   n is 0;-   R³ and R⁴ are each independently —N(R⁷)₂;-   R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    haloalkyl, —OR⁶, —R⁸—OR⁶, and —N(R⁷)₂, morpholinyl, piperidinyl,    piperazinyl (optionally substituted by alkyl);-   R⁶ is hydrogen, alkyl, aryl, or aralkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred set of compounds, preferred compounds are selectedfrom the group consisting of the following:

-   4-(benzo[1,3]dioxol-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(5-methoxybenzothiazol-2-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(benzothiazol-2-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(4H-[1,2,4]-triazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(1H-pyrazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(pyridin-4-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(9-ethyl-9H-carbazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(6-methoxypyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(1H-indazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(quinolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(6-chloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(isoquinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(quinolin-3-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(benzo[1,2,5]thiadiazol-4-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(quinolin-8-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(quinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(2H-benzotriazol-5-yl)hydrazono]4H-pyrazole-3,5-diamine;-   4-[(2-methyl-2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(benzo[2,1,3]thiadiazol-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   7-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-4-trifuoromethylchroman-2-one;-   4-(quinazolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(1-methyl-1H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-methyl-3H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,2-difluorobenzo[1,3]dioxol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(1,1-dioxo-1H-benzo[b]thiophen-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(phthalazin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(6-(piperidin-1-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(6-(morpholin-4-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[6-(4-methylpiperazin-1-yl)pyridin-3-yl]hydrazono}-4H-pyrazole-3,5-diamine;-   2-[{5-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]pyridin-2-yl}(2-hydroxyethyl)amino]ethanol;-   4-[(2,6-dimethoxypyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,6-dichloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(6-fluoropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methylpyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   N,N-dimethyl-4-(quinolin-6-yl-hydrazono)-4H-pyrazole-3,5-diamine;-   4-[(6-chloro-pyridin-3-yl)-hydrazono]-N,N-dimethyl-4H-pyrazole-3,5-diamine;-   4-[(6-fluoro-pyridin-3-yl)-hydrazono]-N,N-dimethyl-4H-pyrazole-3,5-diamine;-   N,N-dimethyl-4-(phthalazin-5-yl-hydrazono)-4H-pyrazole-3,5-diamine;    and-   N,N-dimethyl-4-(pyridin-3-yl-hydrazono)-4H-pyrazole-3,5-diamine.

Of the compounds of formula (I) set forth above in the Summary of theInvention, another preferred group is that group of compounds having thefollowing formula (Ib):

wherein:

-   n is 0 to 5;-   R¹ is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁶;-   R³ and R⁴ are each independently —N(R⁷)₂ or —N(R⁷)C(O)R⁶;-   R⁵ is aryl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, nitro, cyano,    haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶,    —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH,    —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂,    —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂,    —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   or R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl,    heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1    to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶,    —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶,    —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred group of compounds, a preferred subgroup is thatsubgroup of compounds wherein:

-   n is 0;-   R¹ is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁶;-   R³ and R⁴ are each independently —N(R⁷)₂;-   R⁵ is phenyl optionally substituted with one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl,    haloalkoxy, or aryl;-   or R⁵ is pyridinyl;-   R⁶ is alkyl, aryl, or aralkyl; and-   each R⁷ is independently hydrogen or alkyl.

Of this preferred subgroup, preferred compounds are selected from groupconsisting of the following:

-   (3,5-diamino-4-phenylazopyrazol-1-yl)phenylmethanone;-   1-(4-bromophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine;-   4-(3,5-diamino-4-phenylazopyrazol-1-yl)benzoic acid;-   1-(4-fluorophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine;-   1-methyl-4-phenylazo-1H-pyrazole-3,5-diamine;-   1-benzyl-4-phenylazo-1H-pyrazole-3,5-diamine;-   1-{2-[3,5-diamino-4-(pyridin-3-ylazo)pyrazol-1-yl]-2-oxoethyl}pyrrolidine-2-carboxylic    acid methyl ester; and-   4-(isoquinolin-5-ylazo)-1-methyl-1H-pyrazole-3,5-diamine.

Of the compounds of formula (I) set forth above in the Summary of theInvention, a preferred compound is a compound of formula (Ia):

wherein:

-   n is 0;-   R³ and R⁴ are each —NH₂; and-   R⁵ is phenyl substituted at the 4-position by fluoro and at the    3-position by trifluoromethyl, namely,    4-[(4-fluoro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine.

Of the compounds of formula (I) as set forth above in the Summary of theInvention, another group is that group of compounds of formula (I):

wherein:

-   n is 0 to 5;-   R¹ and R² are each independently hydrogen, alkyl, aryl, aralkyl or    —C(O)R⁶;-   or R¹ and R² can each independently be a part of a double bond    within the pyrazole ring;-   R³ and R⁴ are each independently —N(R⁷)₂ or —N(R⁷)C(O)R⁶;-   R⁵ is phenyl substituted with one or more substituents selected from    the group consisting of alkyl, halo, nitro, cyano, haloalkyl,    haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶, —R⁸—OR⁶,    —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where    t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂,    —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and    —N(R⁹)C(O)R⁶;-   or R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl,    heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to    4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶,    —S(O)_(t)N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂,    —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl;-   provided that when n is 0, R¹ is phenyl, R² is hydrogen, R³ and R⁴    are both —NH₂, R⁵ can not be unsubstituted phenyl; and-   provided that when n is 0, R¹ and R² are both hydrogen, and R³ and    R⁴ are both —NH₂, R⁵ can not be phenyl, naphth-2-yl, pyridin-3-yl,    3-methoxyphenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl,    2-chlorophenyl, 3-nitrophenyl,-   4-aminosulfonylphenyl, or 4-(pyrimidin-2-yl)aminosulfonylphenyl;-   as a single stereoisomer, a mixture of stereoisomers, a solvate or a    polymorph; or a pharmaceutically acceptable salt thereof.

Of this preferred group of compounds, a preferred subgroup is thatsubgroup of compounds wherein R¹ and R² are each part of a double bondof the pyrazole ring, i.e., compounds of formula (Ia):

wherein:

-   n is 0 to 5;-   R³ and R⁴ are each independently —NH₂;-   R⁵ is phenyl substituted with one or more substituents selected from    the group consisting of alkyl, halo, nitro, cyano, haloalkyl,    haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶, —R⁸—OR⁶,    —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where    t is 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂,    —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and    —N(R⁹)C(O)R⁶;-   or R⁵ is heterocyclyl optionally substituted with one or more    substituents selected from the group consisting of alkyl, halo,    nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl,    heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to    4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶,    —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶,    —C(O)N(R⁶)₂, —N(R⁷)₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶, wherein the    heterocyclyl is selected from the group consisting of pyridinyl,    indazolyl, quinolinyl, isoquinolyl, benzothiadiazolyl,    benzotriazolyl, pyrazolyl, quinazolinyl, benzodioxolyl,    benzodioxinyl, benzothiophenyl, phthalazinyl, piperidinyl,    morpholinyl, and piperazinyl;-   each R⁶ is independently hydrogen, alkyl, aryl, aralkyl,    hetereocyclyl or heterocyclylalkyl;-   each R⁷ is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl,    heterocyclyl, heterocyclylalkyl, or —R⁸—OR⁹;-   each R⁸ is a straight or branched alkylene chain; and-   each R⁹ is hydrogen or alkyl.

Of this preferred subgroup of compounds, preferred compounds areselected from the group consisting of the following:

-   4-[(3-trifluoromethoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-chloro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-benzylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(4-(phenyl)phenylhydrazono)-4H-pyrazole-3,5-diamine;-   4-{[4-(4-methylaminobenzyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(2,3-difluoro-4-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-fluoro-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   N-ethyl-4-(phenylhydrazono)-4H-pyrazole-3,5-diamine;-   {2-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol;-   {2-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol;-   4-({3-[2-(2-methoxyethoxy)ethoxymethyl]phenyl}hydrazono)-4H-pyrazole-3,5-diamine;-   4-[(4-methoxy-3-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-nitro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-phenylaminophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-diethylaminomethylphenol;-   4-[(2-methyl-5-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   {3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-5-nitrophenyl}methanol;-   4-[(3-diethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-dimethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2,6-dimethylpyrimidin-4-yl)benzenesulfonamide;-   4-[(3-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   1-{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}ethanethione;-   {4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzyl}phosphonic    acid diethyl ester;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   4-[(4-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   N-butyl-3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   4-[(3-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[4-(morpholine-4-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-{[4-(pyrrolidine-1-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(3-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   2-{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanol;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamide;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamide;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamide;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamide;-   3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2-hydroxyethyl)benzenesulfonamide;-   4-[(4-morpholin-4-ylphenyl)hydrazono]4H-pyrazole-3,5-diamine;-   4-[(3-chloro-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-(piperidin-1-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methyl-3-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-methoxy-3-(morpholin-4-yl)methylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-(morpholin-4-yl)methylphenol;-   4-[(2-methyl-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-fluoro-2-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine-   4-[(3-(morpholin-4-ylmethyl)-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine-   4-[(3-fluoro-4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine-   4-[(4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine-   4-{[4-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine-   4-{[3-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine-   4-[(3-(morpholin-4-ylmethyl)-5-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[4-(2-(morpholin-4-yl)ethyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;-   4-[(3-(pyrrolidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(4-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(6-methoxypyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(1H-indazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(quinolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(6-chloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(isoquinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(quinolin-3-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(benzo[1,2,5]thiadiazol-4-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(quinolin-8-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-(quinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2-methyl-2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(benzo[2,1,3]thiadiazol-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   7-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-4-trifluoromethylchroman-2-one;-   4-(quinazolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(1-methyl-1H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(3-methyl-3H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,2-difluorobenzo[1,3]dioxol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(1,1-dioxo-1H-benzo[b]thiophen-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-(phthalazin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;-   4-[(6-(piperidin-1-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(6-(morpholin-4-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-{[6-(4-methylpiperazin-1-yl)pyridin-3-yl]hydrazono}-4H-pyrazole-3,5-diamine;-   2-[{5-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]pyridin-2-yl}(2-hydroxyethyl)amino]ethanol;-   4-[(2,6-dimethoxypyridin-3-yl)hydrazono]4H-pyrazole-3,5-diamine;-   4-[(2,6-dichloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;-   4-[(6-fluoropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine; and-   4-[(4-methylpyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine.

Of the preferred group of compounds as set forth above, anotherpreferred subgroup is that subgroup of compounds having the followingformula (Ib):

wherein:

-   n is 0;-   R¹ is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁶;-   R³ and R⁴ are each independently —N(R⁷)₂;-   R⁵ is phenyl substituted with one or more substituents selected from    the group consisting of alkyl, halo, haloalkyl, haloalkoxy, or aryl;-   or R⁵ is pyridinyl;-   R⁶ is alkyl, aryl, or aralkyl; and-   each R⁷ is independently hydrogen or alkyl.

Of this preferred subgroup of compounds, preferred compounds areselected from group consisting of the following:

-   1-benzyl-4-phenylazo-1H-pyrazole-3,5-diamine;-   1-{2-[3,5-diamino-4-(pyridin-3-ylazo)pyrazol-1-yl]-2-oxoethyl}pyrrolidine-2-carboxylic    acid methyl ester; and-   4-(isoquinolin-5-ylazo)-1-methyl-1H-pyrazole-3,5-diamine.

Of the compounds of formula (Ic) as set forth above in the Summary ofthe Invention, a preferred group of compounds is that subgroup ofcompounds wherein:

-   R^(1c) and R^(4c) are each hydrogen; and-   R^(2c) is aryl (optionally substituted with one or more substituents    selected from the group consisting of halo, alkoxy, nitro,    haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl).

Of this group of compounds, a preferred subgroup of compounds is thatsubgroup of compounds of formula (Ic) wherein:

-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl); and-   R^(5c) is aryl (optionally substituted by one or more substituents    selected from the group consisting of alkyl, alkoxy, halo,    haloalkyl, haloalkoxy, haloalkylthio, arylthioalkyl (wherein the    aryl group is optionally substituted with one or more halo groups),    nitro, —C(O)OR^(7c), and —N(R^(7c))—C(O)—R^(7c)).

Of this subgroup of compounds, a preferred class of compounds is thatclass of compounds wherein:

-   R^(5c) is phenyl (optionally substituted by one or more substituents    selected from the group consisting of alkyl, alkoxy, halo,    haloalkyl, haloalkoxy, haloalkylthio, phenylthioalkyl (wherein the    phenyl group is optionally substituted with one or more halo    groups), nitro, —C(O)OR^(7c), and —N(R^(7c))—C(O)—R^(7c)).

Of this class of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-phenyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-m-tolyl-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-p-tolyl-4H-pyrazol-3-ylamine;-   5-(3-chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-(4-chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(3-trifluoromethylphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(4-trifluoromethoxyphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(4-methoxyphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-m-tolyl-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-p-tolyl-4H-pyrazol-3-ylamine;-   5-(3-chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-(4-chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(3-trifluoromethylphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(4-trifluoromethoxyphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(4-methoxyphenyl)-4H-pyrazol-3-ylamine;-   (2-morpholin-4-ylethyl)[5-phenyl-4-(phenylhydrazono)-4H-pyrazol-3-yl]amine;-   N-[5-phenyl-4-(phenylhydrazono)-4H-pyrazol-3-yl]nicotinamide;-   5-(2-fluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3,4-dimethoxyphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-yl}benzoic    acid;-   5-(2-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(4-chloro-3-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-fluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(4-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-bromophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(4-fluoro-3-methylphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(4-fluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3,4-difluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-fluoro-4-methylphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3,4-dimethylphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-(2-trifluoromethoxyphenyl)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-(4-trifluoromethylsulfanylphenyl)-4H-pyrazol-3-ylamine;-   5-(3,5-difluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-(4-trifluoromethylphenyl)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-(3,4,5-trimethoxyphenyl)-4H-pyrazol-3-ylamine;-   5-[3-(4-chlorophenylsulfanylmethyl)phenyl]-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;    and-   N-{4-[5-amino-4-(phenylhydrazono)-4H-pyrazol-3-yl]phenyl}acetamide.

Particularly preferred is

-   5-(4-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine.

Another preferred subgroup of the preferred group of compounds is thatsubgroup of compounds wherein:

-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl); and-   R^(5c) is aralkyl (wherein the aryl group is optionally substituted    by one or more substituents selected from the group consisting of    alkyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkylthio,    arylthioalkyl (wherein the aryl group is optionally substituted with    one or more halo groups) or aralkenyl (wherein the aryl group is    optionally substituted by one or more halo groups).

Of this subgroup of compounds, a preferred class of compound is thatclass of compounds wherein:

-   R^(5c) is phenylalkyl (wherein the phenyl group is optionally    substituted by one or more substituents selected from the group    consisting of alkyl, alkoxy, halo, haloalkyl, haloalkoxy,    haloalkylthio, phenylthioalkyl (wherein the phenyl group is    optionally substituted with one or more halo groups) or    phenylalkenyl (wherein the phenyl group is optionally substituted by    one or more halo groups).

Of this class of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-(4-methoxybenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-phenethyl-4H-pyrazol-3-ylamine;-   4-[(3-chlorophenyl)hydrazono]-5-phenethyl-4H-pyrazol-3-ylamine;-   4-[(3,5-difluorophenyl)hydrazono]-5-phenethyl-4H-pyrazol-3-ylamine;-   5-(4-chlorobenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzhydryl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2,5-dimethoxy-benzyl)-4-(phenyl-hydrazono)-4H-pyrazol-3-ylamine;-   5-(3,4-dimethoxybenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-phenethyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine; and-   5-(3-ethyl-benzyl)-4-(phenyl-hydrazono)-4H-pyrazol-3-ylamine.

Another preferred subgroup of compounds is that subgroup wherein

-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl); and-   R^(5c) is heterocyclyl (optionally substituted by one or more    substituents selected from the group consisting of alkyl, halo,    haloalkyl, alkylthio, and aryl (optionally substituted with one or    more halo groups)).

Of this subgroup of compounds, a preferred class is that class ofcompounds wherein R^(5c) is a heterocyclyl selected from the groupconsisting of piperidinyl, morpholinyl, pyrrolidinyl, furanyl,isooxazolyl, pyridinyl, thienyl, pyrrolyl, quinolinyl, benzothienyl,benzodioxolyl, benzooxadiazolyl, pyrazolyl, thiadiazolyl, andquinoxalinyl.

Of this class of compounds, preferred compounds are selected from thegroup consisting of the following:

-   4-[(3-fluorophenyl)hydrazono]-5-furan-2-yl-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(2-methylfuran-3-yl)-4H-pyrazol-3-ylamine;-   5-(2,5-dimethyl-furan-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   5-(2-chloro-6-methylpyridin-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3,5-dimethylisoxazol-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(1-methyl-1H-pyrrol-2-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-thiophen-3-yl-4H-pyrazol-3-ylamine;-   5-(5-methyl-2-trifluoromethylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-tert-butyl-5-methylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-methylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-furan-2-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-quinolin-6-yl-4H-pyrazol-3-ylamine;-   5-[5-(4-chlorophenyl)-2-methylfuran-3-yl]-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzo[b]thiophen-3-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   2-{3-[N′-(3-amino-5-pyridin-4-yl-pyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanol;-   4-[(3-fluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[1′-(3-amino-5-pyridin-4-ylpyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   5-(2-chloropyridin-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzo[1,3]dioxol-5-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzo[1,2,5]oxadiazol-5-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(5-bromopyridin-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-morpholin-4-ylmethylphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   5-(2-methylsulfanylpyridin-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(6-chloropyridin-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzo[b]thiophen-2-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   1′-phenyl-4-(phenylhydrazono)-5′-propyl-4H,1H-[3,4′]bipyrazolyl-5-ylamine;-   5-(4-methyl-[1,2,3]thiadiazol-5-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-quinoxalin-2-yl-4H-pyrazol-3-ylamine;-   2′,5′-dimethyl-4-(phenylhydrazono)-4H,2′H-[3,3′]bipyrazolyl-5-ylamine;-   5-(5-methyl-3-phenylisoxazol-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3,4-difluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3,4-difluoro-phenyl)-hydrazono]-5-pyridin-3-yl-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-pyridin-3-yl-4H-pyrazol-3-ylamine;-   5-(3-chlorothiophen-2-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   {4-[(3-fluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-yl}methylamine;-   {4-[(3,4-difluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-yl}methylamine;-   4-(phenylhydrazono)-5-thiophen-2-yl-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-pyridin-2-yl-4H-pyrazol-3-ylamine;-   5-(3-methoxythiophen-2-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-morpholin-4-yl-4-(phenyl-hydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine;-   4-{N′-[3-amino-5-(4-methylpiperazin-1-yl-pyrazol-4-ylidene]-hydrazino}-benzenesulfonamide;-   4-[N′-(3-amino-5-pyrrolidin-1-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide;-   5-(4-methylpiperazin-1-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine    dihydrochloride;-   5-pyrrolidin-1-yl-4-[(3-trifluoromethyl-phenyl)-hydrazono]-4H-pyrazol-3-ylamine;-   3-[N′-(3-amino-5-pyrrolidin-1-yl-pyrazol-4-ylidene)-hydrazino]-N-methyl-benzenesulfonamide;-   3-[N′-(3-amino-5-pyrrolidin-1-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide;-   4-[(3-fluoro-phenyl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine;-   5-pyrrolidin-1-yl-4-[(3-pyrrolidin-1-ylmethyl-phenyl)-hydrazono]-4H-pyrazol-3-ylamine;-   4-[(3-dimethylaminomethylphenyl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3-morpholin-4-ylmethyl-phenyl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine;-   4-[(3-fluoro-4-methoxyphenyl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine;-   3-[N′-(3-amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide;-   3-[N′-(3-amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-N-methyl-benzenesulfonamide;    and-   3-[N′-(3-amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-N-(2-hydroxyethyl)-benzenesulfonamide.

Particularly preferred are those compounds selected from the groupconsisting of the following:

-   4-[(3-fluorophenyl)hydrazono]-5-furan-2-yl-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-thiophen-3-yl-4H-pyrazol-3-ylamine;-   5-furan-2-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   2-{3-[N′-(3-amino-5-pyridin-4-yl-pyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanol;-   4-[(3-fluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[N′-(3-amino-5-pyridin-4-yl-pyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   4-[(3-morpholin-4-ylmethylphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3,4-difluoro-phenyl)-hydrazono]-5-pyridin-3-yl-4H-pyrazol-3-ylamine;    and-   4-(phenylhydrazono)-5-pyridin-3-yl-4H-pyrazol-3-ylamine.

Another preferred subgroup of compounds is that subgroup of compoundswherein

-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,-   —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl); and-   R^(5c) is heterocyclylalkyl selected from the group consisting of    the following: isoindoledionylalkyl, morpholinylalkyl, and    triazolylalkyl.

Of this subgroup of compounds, preferred compounds are selected from thegroup consisting of the following:

-   2-{5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isoindole-1,3-dione;-   2-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isoindole-1,3-dione;-   4-[(3-fluorophenyl)hydrazono]-5-morpholin-4-ylmethyl-4H-pyrazol-3-ylamine;-   4-[(3,4-difluorophenyl)hydrazono]-5-morpholin-4-ylmethyl-4H-pyrazol-3-ylamine;-   5-(1-methyl-1-[1,2,4]triazol-1-ylethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-morpholin-4-ylethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[((3-fluorophenyl)hydrazono]-5-(3-morpholin-4-yl-propyl)-4H-pyrazol-3-ylamine;    and-   5-(4-morpholin-4-ylbutyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine.

Particularly preferred is4-[(3-fluorophenyl)hydrazono]-5-morpholin-4-yl-methyl-4H-pyrazol-3-ylamine.

Another preferred subgroup is that subgroup of compounds of formula (Ic)wherein:

-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl); and-   R^(5c) is hydrogen, alkyl, alkenyl, or cycloalkyl (optionally    substituted by one or more substituents selected from the group    consisting of alkyl and phenyl);-   R^(6c) is a straight or branched alkylene chain.

Of this subgroup of compounds, a preferred class of compounds are thosecompounds wherein the compound is selected from the group consisting ofthe following:

-   tert-butyl-[5-methyl-4-(phenylhydrazono)-4H-pyrazol-3-yl]amine;-   4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-methyl-4-(phenyl-hydrazono)-4H-pyrazol-3-ylamine;-   4-(3-fluorophenylhydrazono)-5-methyl-2H-pyrazol-3-ylamine-   4-[(3-chlorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-ylamine;-   4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-tert-butyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   4-[(3,4-difluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-ylamine;-   5-methyl-4-[(4-trifluoromethylphenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-methyl-4-[(3-nitrophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-[(3-nitrophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   {4-[(3,4-difluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}ethylamine;-   5-ethyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   ethyl-{4-[(3-fluoro-phenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}amine;-   {4-[(3,4-difluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}methylamine;-   4-[N′-(3-aminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   5-cyclopropyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-isopropyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2,2-dimethylpropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-phenylcyclopropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(1-ethylpropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-isobutyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   {4-[(3-fluorophenyl)-hydrazono]-5-methyl-4H-pyrazol-3-yl}methylamine;-   4-[(4-methoxyphenyl)hydrazono]-5-methyl-4H-pyrazol-3-ylamine;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-2-chloro-6-methyl-nicotinamide;-   3-[N′-(3-amino-5-cyclopropylpyrazol-4-ylidene)hydrazino]-n-(2-hydroxyethyl)-benzenesulfonamide;    and-   3-[N-(3-amino-5-cyclopropylpyrazol-4-ylidene)hydrazino]benzenesulfonamide.

Particularly preferred are those compounds selected from the groupconsisting of the following:

-   4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-methyl-4-[(3-nitrophenyl)hydrazono]-4H-pyrazol-3-ylamine; and-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-4H-pyrazol-3-ylamine.

Another preferred subgroup of the compounds of formula (Ic is thatsubgroup wherein:

-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   R^(5c) is —R^(6c)—O—R^(12c), —R⁶—S—R^(12c), —R^(6c)—N(R^(9c))₂;-   each R^(9c) is independently hydrogen, alkyl, aryl, aralkyl,    heterocyclylalkyl, —C(O)—R^(11c), —C(O)—R^(10c)—C(O)OR^(7c),    —R^(10c)—C(O)OR^(7c), or —S(O)₂—R^(7c);-   each R^(10c) is independently a direct bond, straight or branched    alkylene chain or straight or branched alkenylene chain;-   R^(11c) is aryl (optionally substituted by one or more substituents    selected from the group consisting of alkyl and halo), heterocyclyl    (optionally substituted by one or more substituents selected from    the group consisting of —C(O)OR^(7c) and —C(O)N(R^(7c))₂) or    heterocyclylalkyl (optionally substituted by one or more    substituents selected from the group consisting of —C(O)OR^(7c) and    —C(O)N(R^(7c))₂); and-   each R^(12c) is independently aryl or aralkyl (optionally    substituted by one or more substituents selected from group    consisting of halo and nitro).

A preferred class of compounds of this subgroup of compounds is thatclass of compounds wherein the compound is a compound of formula (Ic)wherein R^(5c) is —R^(6c)—O—R^(12c) or —R^(6c)—S—R^(12c).

Of this class of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-(4-chlorophenoxymethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-phenoxypropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-methylsulfanylethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;    and-   5-(2-nitrophenoxymethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine.

Another preferred class of compounds is that class of compounds offormula (Ic) wherein:

-   R^(5c) is —R^(6c)—N(R^(9c))₂; and-   one R^(9c) is hydrogen and the other R^(9c) is hydrogen, alkyl,    aryl, aralkyl, heterocyclylalkyl, —C(O)—R^(11c),    —C(O)—R^(10c)—C(O)OR^(7c), —R^(10c)—C(O)OR^(7c), or —S(O)₂—R^(7c).

Of this class of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   3-({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)acrylic    acid;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isonicotinamide;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}nicotinamide;-   1-[({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)methyl]pyrrolidine-2-carboxylic    acid methyl ester;-   1-[3-({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)acryloyl]-pyrrolidine-2-carboxylic    acid methyl ester;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}methanesulfonamide;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}succinamic    acid;-   1-[({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)methyl]pyrrolidine-2-carboxylic    acid;-   N-{5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}nicotinamide;-   4-[(3,4-difluorophenyl)-hydrazono]-5-[(2-morpholin-4-ylethylamino)methyl]-4H-pyrazol-3-yl-amine;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-4-fluorobenzenesulfonamide;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}malonamic    acid benzyl ester;-   butane-1-sulfonic acid    {5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}amide;-   N-{5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-2-chloro-6-methyl-nicotinamide;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-2-chloro-6-methyl-nicotinamide;    and-   5-(3-aminopropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine.

Another preferred class of compounds is that class of compounds offormula (Ic) wherein:

-   R^(5c) is —R^(6c)—N(R^(9c))₂; and-   each R^(9c) is the same and selected from the group consisting of    heterocyclylalkyl and —R^(10c)—C(O)OR^(7c).

Of this class of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-{[bis-(2-morpholin-4-ylethyl)amino]methyl}-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-[(bis-pyridin-3-ylmethylamino)methyl]-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-[(bis-pyridin-2-ylmethylamino)methyl]-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;    and-   ({5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}ethoxycarbonylmethylamino)-acetic    acid ethyl ester.

Another preferred subgroup of compounds of formula (Ic) is that subgroupof compounds wherein:

-   R^(1c) and R^(4c) are each hydrogen; and-   R^(2c) is N-heterocyclyl (optionally substituted one or more    substituents selected from the group consisting of alkyl, halo, and    —C(O)OR^(7c)).

Of this preferred subgroup, a preferred class of compounds of formula(Ic) is that subgroup of compounds wherein:

-   R^(2c) is N-heterocyclyl selected from the group consisting of    pyridinyl, thiazolyl, tetrazolyl, pyrazolyl, isoquinolinyl,    quinolinyl, and phthalazinyl;-   R^(3c) is hydrogen or alkyl; and-   R^(5c) is hydrogen, alkyl, alkenyl, —R^(6c)—NH₂, cycloalkyl,    phenylalkyl (wherein the phenyl group is optionally substituted by    one or more substituents selected from the group consisting of    alkoxy and halo), or heterocyclyl selected from the group consisting    of morpholin-4-yl, piperidin-4-yl, pyridin-4-yl, thien-2-yl,    pyrrolyl, and pyrrolidin-2-yl.

Of this class of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-methyl-4-[(4H-[1,2,4]triazol-3-yl)hydrazono]-4H-pyrazol-3-ylamine;-   5-methyl-4-[(2H-tetrazol-5-yl)hydrazono]-4H-pyrazol-3-ylamine;-   3-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-1H-pyrazole-4-carboxylic    acid ethyl ester;-   3-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-1H-pyrazole-4-carboxylic    acid;-   5-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-2H-[1,2,3]triazole-4-carboxylic    acid;-   4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(4-methoxybenzyl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-tert-butyl-4-[(1H-tetrazol-5-yl)hydrazono]-4H-pyrazol-3-ylamine;-   4-(isoquinolin-5-ylhydrazono)-5-phenethyl-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-(isoquinolin-5-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-aminomethyl-4-(isoquinolin-5-ylhydrazono)-4H-pyrazol-3-ylamine;-   4-(isoquinolin-5-ylhydrazono)-5-methyl-4H-pyrazol-3-ylamine;-   5-methyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-(quinolin-6-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   ethyl-[5-methyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-yl]amine;-   4-(isoquinolin-5-ylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   5-pyridin-4-yl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-methyl-4-(phthalazin-5-ylhydrazono)-4H-pyrazol-3-ylamine;-   methyl-[4-(phthalazin-5-ylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-yl]amine;-   4-(pyridin-3-yl-hydrazono)-5-thiophen-2-yl-4H-pyrazol-3-ylamine;-   5-(1-methyl-1H-pyrrol-2-yl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-(1-methyl-1H-pyrrol-2-yl)-4-(quinolin-6-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-cyclopropyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-morpholin-4-yl-4-(pyridin-3-yl-hydrazono)-4H-pyrazol-3-ylamine;-   4-[(6-chloropyridin-3-yl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine;-   5-pyrrolidin-1-yl-4-(quinolin-6-yl-hydrazono)-4H-pyrazol-3-ylamine;-   4-[(6-chloro-pyridin-3-yl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine;-   4-[(6-fluoro-pyridin-3-yl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine;-   5-morpholin-4-yl-4-(phthalazin-5-yl-hydrazono)-4H-pyrazol-3-ylamine;    and-   4-[(6-methyl-pyridin-3-yl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine.

Particularly preferred are those compounds selected from the groupconsisting of the following:

-   5-(4-methoxybenzyl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   4-(isoquinolin-5-ylhydrazono)-5-methyl-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   4-(isoquinolin-5-ylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   5-pyridin-4-yl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-methyl-4-(phthalazin-5-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-(1-methyl-1H-pyrrol-2-yl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;    and-   5-(1-methyl-1H-pyrrol-2-yl)-4-(quinolin-6-ylhydrazono)-4H-pyrazol-3-ylamine.

Another preferred class of compounds is that class of compounds offormula (Ic) wherein:

-   R^(2c) is N-heterocyclyl selected from the group consisting of    pyridinyl, thiazolyl, tetrazolyl, pyrazolyl, isoquinolinyl,    quinolinyl, and phthalazinyl;-   R^(3c) is hydrogen or alkyl; and-   R^(5c) is phenyl (optionally substituted by one or more substituents    selected from the group consisting of alkoxy and halo).

A preferred compound of this class is

-   5-(2-fluorophenyl)-4-(phthalazin-5-ylhydrazono)-4H-pyrazol-3-ylamine.

Another preferred group of compounds of formula (I) is that group ofcompounds having formula (Ic)

as a single tautomer, a mixture of tautomers, a single stereoisomer, amixture of stereoisomers, or a racemic mixture; or a pharmaceuticallyacceptable salt or solvate thereof; wherein:

-   R^(1c) is hydrogen, alkyl, aryl or aralkyl;-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   R^(3c) is hydrogen, alkyl, heterocyclylalkyl, or    heterocyclylcarbonyl;-   R^(4c) is hydrogen or alkyl;-   R^(5c) is aryl (optionally substituted by one or more substituents    selected from the group consisting of alkoxy, halo, haloalkyl,    haloalkoxy, haloalkylthio, arylthioalkyl (wherein the aryl group is    optionally substituted with one or more halo groups), nitro,    —C(O)OR^(7c), and —N(R^(7c))—C(O)—R^(7c));-   R^(6c) is a straight or branched alkylene chain:-   each R^(7c) is independently hydrogen, alkyl, aryl, aralkyl or    heterocyclylakyl; and-   R^(8c) is hydrogen, alkyl, aryl, aralkyl or hydroxyalkyl.

Of this group of compounds, a preferred subgroup is that subgroup ofcompounds wherein:

-   R^(1c) and R^(4c) are each hydrogen;-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl); and-   R^(5c) is phenyl (optionally substituted by one or more substituents    selected from the group consisting of alkoxy, halo, haloalkyl,    haloalkoxy, haloalkylthio, phenylthioalkyl (wherein the phenyl group    is optionally substituted with one or more halo groups), nitro,    —C(O)OR^(7c), and —N(R^(7c))—C(O)—R^(7c)).

Of this preferred subgroup, preferred compounds are selected from thegroup consisting of the following:

-   5-phenyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-m-tolyl-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-p-tolyl-4H-pyrazol-3-ylamine;-   5-(3-chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-(4-chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(3-trifluoromethylphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(4-trifluoromethoxyphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(4-methoxyphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-m-tolyl-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-p-tolyl-4H-pyrazol-3-ylamine;-   5-(3-chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-(4-chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(3-trifluoromethylphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(4-trifluoromethoxyphenyl)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(4-methoxyphenyl)-4H-pyrazol-3-ylamine;-   (2-morpholin-4-ylethyl)[5-phenyl-4-(phenylhydrazono)-4H-pyrazol-3-yl]amine;-   N-[5-phenyl-4-(phenylhydrazono)-4H-pyrazol-3-yl]nicotinamide;-   5-(2-fluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3,4-dimethoxyphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-yl}benzoic    acid;-   5-(2-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(4-chloro-3-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-fluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(4-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-bromophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(4-fluoro-3-methylphenyl)-4-(phenylhydrazono)₄H-pyrazol-3-ylamine;-   5-(4-fluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3,4-difluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-fluoro-4-methylphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3,4-dimethylphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-(2-trifluoromethoxyphenyl)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-(4-trifluoromethylsulfanylphenyl)-4H-pyrazol-3-ylamine;-   5-(3,5-difluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-(4-trifluoromethylphenyl)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-(3,4,5-trimethoxyphenyl)-4H-pyrazol-3-ylamine;-   5-[3-(4-chlorophenylsulfanylmethyl)phenyl]-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;    and-   N-{4-[5-amino-4-(phenylhydrazono)-4H-pyrazol-3-yl]phenyl}acetamide.

Particularly preferred is5-(4-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine.

Another preferred group of compounds of formula (Ic) is that group ofcompounds having the following formula (Ic):

as a single tautomer, a mixture of tautomers, a single stereoisomer, amixture of stereoisomers, or a racemic mixture; or a pharmaceuticallyacceptable salt or solvate thereof; wherein:

-   R^(1c) is hydrogen, alkyl, aryl or aralkyl;-   R^(2c) is aryl (optionally substituted with one or more substituents    selected from the group consisting of halo, alkoxy, nitro,    haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   R^(3c) is hydrogen, alkyl, heterocyclylalkyl, or    heterocyclylcarbonyl;-   R^(4c) is hydrogen or alkyl;-   R^(5c) is aralkyl (wherein the aryl group is optionally substituted    by one or more substituents selected from the group consisting of    alkyl, alkoxy, halo, haloalkyl, haloalkoxy, haloalkylthio,    arylthioalkyl (wherein the aryl group is optionally substituted with    one or more halo groups) or aralkenyl (wherein the aryl group is    optionally substituted by one or more halo groups);-   R^(6c) is a straight or branched alkylene chain;-   R^(7c) is hydrogen, alkyl, aryl, aralkyl or heterocyclylakyl; and-   R^(8c) is hydrogen, alkyl, aryl, aralkyl or hydroxyalkyl, provided    that when R^(1c), R^(3c) and R^(4c) are all hydrogen and R^(2c) is    unsubstituted phenyl, R^(5c) can not be unsubstituted benzyl.

Of this group of compounds, a preferred subgroup is that subgroupwherein:

-   R^(1c) and R^(4c) are each hydrogen;-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—COH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl); and-   R^(5c) is phenylalkyl (wherein the phenyl group is optionally    substituted by one or more substituents selected from the group    consisting of alkyl, alkoxy, halo, haloalkyl, haloalkoxy,    haloalkylthio, phenylthioalkyl (wherein the phenyl group is    optionally substituted with one or more halo groups) or    phenylalkenyl (wherein the phenyl group is optionally substituted by    one or more halo groups).

Of this subgroup of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-(4-methoxybenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-phenethyl-4H-pyrazol-3-ylamine;-   4-[(3-chlorophenyl)hydrazono]-5-phenethyl-4H-pyrazol-3-ylamine;-   4-[(3,5-difluorophenyl)hydrazono]-5-phenethyl-4H-pyrazol-3-ylamine;-   5-(4-chlorobenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzhydryl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2,5-dimethoxy-benzyl)-4-(phenyl-hydrazono)-4H-pyrazol-3-ylamine;-   5-(3,4-dimethoxybenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-phenethyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine; and-   5-(3-ethyl-benzyl)-4-(phenyl-hydrazono)-4H-pyrazol-3-ylamine.

Another preferred group of compounds of formula (Ic) is that group ofcompounds having the formula (Ic):

as a single tautomer, a mixture of tautomers, a single stereoisomer, amixture of stereoisomers, or a racemic mixture; or a pharmaceuticallyacceptable salt or solvate thereof; wherein:

-   R^(1c) is hydrogen, alkyl, aryl or aralkyl;-   R^(2c) is aryl (optionally substituted with one or more substituents    selected from the group consisting of halo, alkoxy, nitro,    haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   R^(3c) is hydrogen, alkyl, heterocyclylalkyl, or    heterocyclylcarbonyl;-   R^(4c) is hydrogen or alkyl;-   R^(5c) is heterocyclyl (optionally substituted by one or more    substituents selected from the group consisting of alkyl, halo,    haloalkyl, alkylthio, and aryl (optionally substituted with one or    more halo groups));-   R^(6c) is a straight or branched alkylene chain;-   R^(7c) is hydrogen, alkyl, aryl, aralkyl or heterocyclylakyl; and-   R^(8c) is hydrogen, alkyl, aryl, aralkyl or hydroxyalkyl;-   provided that when R^(1c), R^(3c), and R^(4c) is hydrogen, and    R^(2c) is unsubstituted phenyl, R^(5c) can not be pyrazolonyl,    benzothiazolyl or thioxotriazinyl.

Of this group of compounds, a preferred subgroup is that subgroupwherein R^(5c) is a heterocyclyl selected from the group consisting ofpiperidinyl, morpholinyl, pyrrolidinyl, furanyl, isooxazolyl, pyridinyl,thienyl, pyrrolyl, quinolinyl, benzothienyl, benzodioxolyl,benzooxadiazolyl, pyrazolyl, thiadiazolyl, and quinoxalinyl.

Of this subgroup of compounds, preferred compounds are selected from thegroup consisting of the following:

-   4-[(3-fluorophenyl)hydrazono]-5-furan-2-yl-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(2-methylfuran-3-yl)-4H-pyrazol-3-ylamine;-   5-(2,5-dimethyl-furan-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   5-(2-chloro-6-methylpyridin-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3,5-dimethylisoxazol-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(1-methyl-1H-pyrrol-2-yl)-4-(phenylhydrazono)₄H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-thiophen-3-yl-4H-pyrazol-3-ylamine;-   5-(5-methyl-2-trifluoromethylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-tert-butyl-5-methylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-methylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-furan-2-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-quinolin-6-yl-4H-pyrazol-3-ylamine;-   5-[5-(4-chlorophenyl)-2-methylfuran-3-yl]-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzo[b]thiophen-3-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   2-{3-[N′-(3-amino-5-pyridin-4-yl-pyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanol;-   4-[(3-fluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[N′-(3-amino-5-pyridin-4-yl-pyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   5-(2-chloropyridin-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzo[1,3]dioxol-5-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzo[1,2,5]oxadiazol-5-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(5-bromopyridin-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-morpholin-4-ylmethylphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   5-(2-methylsulfanylpyridin-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(6-chloropyridin-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-benzo[b]thiophen-2-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   1′-phenyl-4-(phenylhydrazono)-5′-propyl-4H,    1′H-[3,4′]bipyrazolyl-5-ylamine;-   5-(4-methyl-[1,2,3]thiadiazol-5-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-quinoxalin-2-yl-4H-pyrazol-3-ylamine;-   2′,5′-dimethyl-4-(phenylhydrazono)-4H,2′H-[3,3′]bipyrazolyl-5-ylamine;-   5-(5-methyl-3-phenylisoxazol-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3,4-difluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3,4-difluoro-phenyl)-hydrazono]-5-pyridin-3-yl-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-pyridin-3-yl-4H-pyrazol-3-ylamine;-   5-(3-chlorothiophen-2-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   {4-[(3-fluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-yl}methylamine;-   {4-[(3,4-difluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-yl}methylamine;-   4-(phenylhydrazono)-5-thiophen-2-yl-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-pyridin-2-yl-4H-pyrazol-3-ylamine;-   5-(3-methoxythiophen-2-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-morpholin-4-yl-4-(phenyl-hydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine;-   4-{N′-[3-amino-5-(4-methylpiperazin-1-yl)-pyrazol-4-ylidene]-hydrazinol}-benzenesulfonamide;-   4-[N′-(3-amino-5-pyrrolidin-1-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide;-   5-(4-methylpiperazin-1-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine    dihydrochloride;-   5-pyrrolidin-1-yl-4-[(3-trifluoromethyl-phenyl)-hydrazono]-4H-pyrazol-3-ylamine;-   3-[N′-(3-amino-5-pyrrolidin-1-yl-pyrazol-4-ylidene)-hydrazino]-N-methyl-benzenesulfonamide;-   3-[N′-(3-amino-5-pyrrolidin-1-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide;-   4-[(3-fluoro-phenyl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine;-   5-pyrrolidin-1-yl-4-[(3-pyrrolidin-1-ylmethyl-phenyl)-hydrazono]-4H-pyrazol-3-ylamine;-   4-[(3-dimethylaminomethylphenyl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3-morpholin-4-ylmethyl-phenyl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine;-   4-[(3-fluoro-4-methoxyphenyl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine;-   3-[N′-(3-amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide;-   3-[N′-(3-amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-N-methyl-benzenesulfonamide;    and-   3-[N′-(3-amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-N-(2-hydroxyethyl)-benzenesulfonamide.

Particularly preferred compounds are selected from the group consistingof the following:

-   4-[(3-fluorophenyl)hydrazono]-5-furan-2-yl-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-(phenylhydrazono)-5-thiophen-3-yl-4H-pyrazol-3-ylamine;-   5-furan-2-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   2-{3-[N′-(3-amino-5-pyridin-4-yl-pyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanol;-   4-[(3-fluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[N′-(3-amino-5-pyridin-4-ylpyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   4-[(3-morpholin-4-ylmethylphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   4-[(3,4-difluoro-phenyl)-hydrazono]-5-pyridin-3-yl-4H-pyrazol-3-ylamine;    and-   4-(phenylhydrazono)-5-pyridin-3-yl-4H-pyrazol-3-ylamine.

Another preferred group of compounds of formula (Ic) is that group ofcompounds having the formula (Ic):

as a single tautomer, a mixture of tautomers, a single stereoisomer, amixture of stereoisomers, or a racemic mixture; or a pharmaceuticallyacceptable salt or solvate thereof; wherein:

-   R^(1c) is hydrogen, alkyl, aryl or aralkyl;-   R^(2c) is aryl (optionally substituted with one or more substituents    selected from the group consisting of halo, alkoxy, nitro,    haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   R^(3c) is hydrogen, alkyl, heterocyclylalkyl, or    heterocyclylcarbonyl;-   R^(4c) is hydrogen or alkyl;-   R^(5c) is heterocyclylalkyl selected from the group consisting of    the following: isoindoledionylalkyl, morpholinylalkyl, and    triazolylalkyl;-   R^(6c) is a straight or branched alkylene chain;-   R^(7c) is hydrogen, alkyl, aryl, aralkyl or heterocyclylakyl; and-   R^(8c) is hydrogen, alkyl, aryl, aralkyl or hydroxyalkyl.

Of this group of compounds, preferred compounds are selected from thegroup consisting of the following:

-   2-{5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isoindole-1,3-dione;-   2-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isoindole-1,3-dione;-   4-[(3-fluorophenyl)hydrazono]-5-morpholin-4-ylmethyl-4H-pyrazol-3-ylamine;-   4-[(3,4-difluorophenyl)hydrazono]-5-morpholin-4-ylmethyl-4H-pyrazol-3-ylamine;-   5-(1-methyl-1-[1,2,4]triazol-1-ylethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-morpholin-4-ylethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-fluorophenyl)hydrazono]-5-(3-morpholin-4-yl-propyl)-4H-pyrazol-3-ylamine;    and-   5-(4-morpholin-4-ylbutyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine.

Particularly preferred is4-[(3-fluorophenyl)hydrazono]-5-morpholin-4-yl-methyl-4H-pyrazol-3-ylamine.

Another preferred group of compounds of formula (Ic) is that grouphaving the formula (Ic):

as a single tautomer, a mixture of tautomers, a single stereoisomer, amixture of stereoisomers, or a racemic mixture; or a pharmaceuticallyacceptable salt or solvate thereof; wherein:

-   R^(1c) is hydrogen, alkyl, aryl or aralkyl;-   R^(2c) is aryl (optionally substituted with one or more substituents    selected from the group consisting of halo, alkoxy, nitro,    haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   R^(3c) is hydrogen, alkyl, heterocyclylalkyl, or    heterocyclylcarbonyl;-   R^(4c) is hydrogen or alkyl;-   R^(5c) is hydrogen, alkyl, alkenyl, or cycloalkyl (optionally    substituted by one or more substituents selected from the group    consisting of alkyl and phenyl);-   R^(6c) is a straight or branched alkylene chain;-   R^(7c) is hydrogen, alkyl, aryl, aralkyl or heterocyclylakyl; and-   R^(8c) is hydrogen, alkyl, aryl, aralkyl or hydroxyalkyl,-   provided that when R^(1c), R^(3c), R^(4c) and R^(5c) are all    hydrogen, R^(2c) can not be unsubstituted phenyl and when R^(1c),    R^(3c) and R^(4c) are all hydrogen and R^(5c) is methyl, R^(2c) can    not be phenyl optionally substituted with one or more substituents    selected from the group consisting of chloro, bromo or alkyl.

Preferred compounds of this group of compounds are selected from thegroup consisting of the following:

-   tert-butyl-[5-methyl-4-(phenylhydrazono)-4H-pyrazol-3-yl]amine;-   4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   4-(3-fluorophenylazo)-5-methyl-2H-pyrazol-3-ylamine;-   4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-tert-butyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   4-[(3,4-difluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-ylamine;-   5-methyl-4-[(4-trifluoromethylphenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-methyl-4-[(3-nitrophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-[(3-nitrophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   {4-[(3,4-difluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}ethylamine;-   5-ethyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   ethyl-{4-[(3-fluoro-phenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}amine;-   {4-[(3,4-difluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}methylamine;-   4-[N′-(3-aminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;-   5-cyclopropyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-isopropyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2,2-dimethylpropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-phenylcyclopropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(1-ethylpropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-isobutyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   {4-[(3-fluorophenyl)-hydrazono]-5-methyl-4H-pyrazol-3-yl}methylamine;-   4-[(4-methoxyphenyl)hydrazono]-5-methyl-4H-pyrazol-3-ylamine;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-2-chloro-6-methyl-nicotinamide;-   3-[N′-(3-amino-5-cyclopropylpyrazol-4-ylidene)hydrazino]-N-(2-hydroxyethyl)benzene-sulfonamide;    and-   3-[N-(3-amino-5-cyclopropylpyrazol-4-ylidene)hydrazino]benzenesulfonamide.

Particularly preferred are those compounds selected from the groupconsisting of the following:

-   4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   5-methyl-4-[(3-nitrophenyl)hydrazono]-4H-pyrazol-3-ylamine; and-   4-[(3-fluoro-4-methoxyphenyl)hydrazono]-4H-pyrazol-3-ylamine.

Another preferred group of compounds of formula (Ic) is that group ofcompounds having the formula (Ic):

as a single tautomer, a mixture of tautomers, a single stereoisomer, amixture of stereoisomers, or a racemic mixture; or a pharmaceuticallyacceptable salt or solvate thereof; wherein:

-   R^(1c) is hydrogen, alkyl, aryl or aralkyl;-   R^(2c) is aryl (optionally substituted with one or more substituents    selected from the group consisting of halo, alkoxy, nitro,    haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   R^(4c) is hydrogen or alkyl;-   R^(3c) is hydrogen, alkyl, heterocyclylalkyl, or    heterocyclylcarbonyl;-   R^(5c) is R^(6c)—OR^(12c), R^(6c)—S—R^(12c), —R^(6c)—N(R^(9c))₂;-   each R^(6c) is independently a straight or branched alkylene chain;-   each R^(7c) is independently hydrogen, alkyl, aryl, aralkyl or    heterocyclylakyl;-   R^(8c) is hydrogen, alkyl, aryl, aralkyl or hydroxyalkyl;-   each R^(9c) is independently hydrogen, alkyl, aryl, aralkyl,    heterocyclylalkyl, —C(O)—R^(11c), —C(O)—R^(10c)—C(O)OR^(7c),    —R^(10c)—C(O)OR^(7c), or —S(O)₂—R^(7c);-   each R^(10c) is independently a direct bond, straight or branched    alkylene chain or straight or branched alkenylene chain;-   R^(11c) is aryl (optionally substituted by one or more substituents    selected from the group consisting of alkyl and halo), heterocyclyl    (optionally substituted by one or more substituents selected from    the group consisting of —C(O)OR^(7c) and —C(O)N(R^(7c))₂) or    heterocyclylalkyl (optionally substituted by one or more    substituents selected from the group consisting of —C(O)OR^(7c) and    —C(O)N(R^(7c))₂); and-   each R¹² is independently aryl or aralkyl (optionally substituted by    one or more substituents selected from group consisting of halo and    nitro).

Of this group of compounds, a preferred subgroup of compounds is thtsubgroup wherein:

-   R^(1c) and R^(4c) are each hydrogen;-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl); and-   R^(5c) is —R^(6c)—O—R^(12c) or R^(6c)—S—R^(12c).

Of this subgroup of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-(4-chlorophenoxymethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(3-phenoxypropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;-   5-(2-methylsulfanylethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine;    and-   5-(2-nitrophenoxymethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine.

Another preferred group of compounds is that group wherein:

-   R^(1c) and R^(4c) are each hydrogen;-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   R^(5c) is —R^(6c)—N(R^(9c))₂; and-   one R^(9c) is hydrogen and the other R^(9c) is hydrogen, alkyl,    aryl, aralkyl, heterocyclylalkyl, —C(O)—R^(11c),    —C(O)—R^(10c)—C(O)OR^(7c), —R^(10c)—C(O)OR^(7c), or —S(O)₂—R^(7c).

Of this group of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine;-   3-({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)acrylic    acid;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isonicotinamide;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}nicotinamide;-   1-[({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)methyl]-pyrrolidine-2-carboxylic    acid methyl ester;-   1-[3-({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)acryloyl]-pyrrolidine-2-carboxylic    acid methyl ester;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}methanesulfonamide;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}succinamic    acid;-   1-[({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)methyl]pyrrolidine-2-carboxylic    acid;-   N-{5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}nicotinamide;-   4-[(3,4-difluorophenyl)-hydrazono]-5-[(2-morpholin-4-ylethylamino)methyl]-4H-pyrazol-3-yl-amine;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-4-fluorobenzenesulfonamide;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}malonamic    acid benzyl ester;-   butane-1-sulfonic acid    {5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}amide;-   N-{5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-2-chloro-6-methyl-nicotinamide;-   N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-2-chloro-6-methyl-nicotinamide;    and-   5-(3-aminopropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine.

Another preferred group of compounds of formula (Ic) is that groupwherein:

-   R^(1c) and R^(4c) are each hydrogen;-   R^(2c) is phenyl (optionally substituted with one or more    substituents selected from the group consisting of halo, alkoxy,    nitro, haloalkyl, —R^(6c)—N(R^(8c))₂, —S(O)₂—R^(6c)—OH,    —S(O)₂—N(R^(7c))R^(8c) and heterocyclylalkyl);-   R^(5c) is —R^(5c)—N(R^(9c))₂; and-   each R^(9c) is the same and selected from the group consisting of    heterocyclylalkyl and —R^(10c)—C(O)OR^(7c).

Of this group of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-{[bis-(2-morpholin-4-ylethyl)amino]methyl}-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-yl-amine;-   5-[(bis-pyridin-3-ylmethylamino)methyl]-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-yl    amine;-   5-[(bis-pyridin-2-ylmethylamino)methyl]-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-yl    amine; and-   (5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethylethoxycarbonylmethyl-amino)acetic    acid ethyl ester.

Another preferred group of compounds of formula (Ic) is that group ofcompounds having the formula (Ic):

as a single tautomer, a mixture of tautomers, a single stereoisomer, amixture of stereoisomers, or a racemic mixture; or a pharmaceuticallyacceptable salt or solvate thereof; wherein:

-   R^(1c) is hydrogen, alkyl, aryl or aralkyl;-   R^(2c) is N-heterocyclyl (optionally substituted one or more    substituents selected from the group consisting of alkyl, halo and    —C(O)OR^(7c));-   R^(3c) is hydrogen, alkyl, aryl, aralkyl, heterocyclylalkyl, or    heterocyclylcarbonyl;-   R^(4c) is hydrogen or alkyl;-   R^(5c) is hydrogen, alkyl, alkenyl, —R^(6c)—O—R^(12c),    —R^(6c)—S—R^(12c), —R^(6c)—N(R^(9c))₂, cycloalkyl (optionally    substituted by one or more substituents selected from the group    consisting of alkyl and aryl), aryl (optionally substituted by one    or more substituents selected from the group consisting of alkyl,    alkoxy, halo, haloalkyl, haloalkoxy, haloalkylthio, arylthioalkyl    (wherein the aryl group is optionally substituted with one or more    halo groups), nitro, —C(O)OR^(7c), and —N(R^(7c))—C(O)—R^(7c)),    aralkyl (wherein the aryl group is optionally substituted by one or    more substituents selected from the group consisting of alkyl,    alkoxy, halo, haloalkyl, haloalkoxy, haloalkylthio, arylthioalkyl    (wherein the aryl group is optionally substituted with one or more    halo groups), nitro, —C(O)OR^(7c), and —N(R^(7c))—C(O)—R^(7c)),    aralkenyl (wherein the aryl group is optionally substituted by one    or more halo groups), heterocyclyl (optionally substituted by one or    more substituents selected from the group consisting of alkyl, halo,    haloalkyl, alkylthio, and aryl (optionally substituted with one or    more halo groups)), or heterocyclylalkyl;-   each R^(6c) is independently a straight or branched alkylene chain;-   each R^(7c) is independently hydrogen, alkyl, aryl, aralkyl or    heterocyclylakyl;-   each R^(9c) is independently hydrogen, alkyl, aryl, aralkyl,    heterocyclylalkyl, —C(O)—R^(11c), —C(O)—R^(10c)—C(O)OR^(7c),    —R^(10c)—C(O)OR^(7c), or —S(O)₂—R^(7c);-   each R^(10c) is independently a direct bond, straight or branched    alkylene chain or straight or branched alkenylene chain;-   R^(11c) is aryl (optionally substituted by one or more substituents    selected from the group consisting of alkyl and halo), heterocyclyl    (optionally substituted by one or more substituents selected from    the group consisting of —C(O)OR^(7c) and —C(O)N(R^(7c))₂) or    heterocyclylalkyl (optionally substituted by one or more    substituents selected from the group consisting of —C(O)OR^(7c) and    —C(O)N(R^(7c))₂); and-   each R^(12c) is independently aryl or aralkyl (optionally    substituted by one or more substituents selected from group    consisting of halo and nitro);-   provided that when R^(1c), R^(3c), R^(4c) and R^(5c) are all    hydrogen, R^(2c) can not be thiadiazolyl; and when R^(1c), R^(3c)    and R^(4c) are all hydrogen, R^(2c) and R^(5c) can not be both    pyrazolonyl; and when R^(1c), R^(3c) and R^(4c) are all hydrogen,    and R^(5c) is methyl, R^(2c) can not be optionally substituted    pyrazolyl; and when R^(1c), R^(3c) and R^(4c) are all hydrogen, and    R^(5c) is t-butyl, R^(2c) can not be pyridin-3-yl optionally    substituted with chloro.

Of this preferred group of compounds, a preferred subgroup is thatsubgroup wherein wherein:

-   R^(1c) and R^(4c) are each hydrogen;-   R^(2c) is N-heterocyclyl selected from the group consisting of    pyridinyl, thiazolyl, tetrazolyl, pyrazolyl, isoquinolinyl,    quinolinyl, and phthalazinyl;-   R^(3c) is hydrogen or alkyl; and-   R^(5c) is hydrogen, alkyl, alkenyl, —R^(6c)—NH₂, cycloalkyl,    phenylalkyl (wherein the phenyl group is optionally substituted by    one or more substituents selected from the group consisting of    alkoxy and halo), or heterocyclyl selected from the group consisting    of pyridin-4-yl, thien-2-yl, or pyrrol-2-yl.

Of this group of compounds, preferred compounds are selected from thegroup consisting of the following:

-   5-methyl-4-[(4H-[1,2,4]triazol-3-yl)hydrazono]-4H-pyrazol-3-ylamine;-   5-methyl-4-[(2H-tetrazol-5-yl)hydrazono]-4H-pyrazol-3-ylamine;-   3-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-1H-pyrazole-4-carboxylic    acid ethyl ester;-   3-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-1H-pyrazole-4-carboxylic    acid;-   5-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-2H-[1,2,3]triazole-4-carboxylic    acid;-   5-(4-methoxybenzyl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-tert-butyl-4-[(1H-tetrazol-5-yl)hydrazono]-4H-pyrazol-3-ylamine;-   4-(isoquinolin-5-ylhydrazono)-5-phenethyl-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-(isoquinolin-5-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-aminomethyl-4-(isoquinolin-5-ylhydrazono)-4H-pyrazol-3-ylamine;-   4-(isoquinolin-5-ylhydrazono)-5-methyl-4H-pyrazol-3-ylamine;-   5-methyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-(quinolin-6-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   ethyl-[5-methyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-yl]amine;-   4-(isoquinolin-5-ylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   5-pyridin-4-yl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-methyl-4-(phthalazin-5-ylhydrazono)-4H-pyrazol-3-ylamine;-   methyl-[4-(phthalazin-5-ylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-yl]amine;-   4-(pyridin-3-yl-hydrazono)-5-thiophen-2-yl-4H-pyrazol-3-ylamine;-   5-(1-methyl-1H-pyrrol-2-yl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-(1-methyl-1H-pyrrol-2-yl)-4-(quinolin-6-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-cyclopropyl-4-(pyridin-3-ylhydrazono)₄H-pyrazol-3-ylamine;-   5-morpholin-4-yl-4-(pyridin-3-yl-hydrazono)-4H-pyrazol-3-ylamine;-   4-[(6-chloropyridin-3-yl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine;-   5-pyrrolidin-1-yl-4-(quinolin-6-yl-hydrazono)-4H-pyrazol-3-ylamine;-   4-[(6-chloro-pyridin-3-yl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine;-   4-[(6-fluoro-pyridin-3-yl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine;-   5-morpholin-4-yl-4-(phthalazin-5-yl-hydrazono)-4H-pyrazol-3-ylamine;    and-   4-[(6-methyl-pyridin-3-yl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine.

Particularly preferred are thos compounds selected from the groupconsisting of the following:

-   5-(4-methoxybenzyl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   4-(isoquinolin-5-ylhydrazono)-5-methyl-4H-pyrazol-3-ylamine;-   5-but-3-enyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   4-(isoquinolin-5-ylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine;-   5-pyridin-4-yl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-methyl-4-(phthalazin-5-ylhydrazono)-4H-pyrazol-3-ylamine;-   5-(1-methyl-1H-pyrrol-2-yl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine;    and-   5-(1-methyl-1H-pyrrol-2-yl)-4-(quinolin-6-ylhydrazono)-4H-pyrazol-3-ylamine.

Another preferred group of compounds of formula (Ic) is that groupwherein:

-   R^(1c) and R^(4c) are each hydrogen;-   R^(2c) is N-heterocyclyl selected from the group consisting of    pyridinyl, thiazolyl, tetrazolyl, pyrazolyl, isoquinolinyl,    quinolinyl, and phthalazinyl;-   R^(3c) is hydrogen or alkyl;-   R^(5c) is phenyl (optionally substituted by one or more substituents    selected from the group consisting of alkoxy and halo).

Of this group, a preferred compound is5-(2-fluorophenyl)-4-(phthalazin-5-yl-hydrazono)-4H-pyrazol-3-ylamine.

E. Preparation of the Compounds of the Invention

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocess described below and in the following Preparations and Examplesthe functional groups of intermediate compounds may need to be protectedby suitable protecting groups. Such functional groups include hydroxy,amino, mercapto and carboxylic acid. Suitable protecting groups forhydroxy include trialkylsilyl or diarylalkylsilyl (e.g.,t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R⁸ (where R⁸ is alkyl, aryl or aralkyl), p-methoxybenzyl,trityl and the like. Suitable protecting groups for carboxylic acidinclude alkyl, aryl or aralkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein.

The use of protecting groups is described in detail in Green, T. W. andP. G. M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed.,Wiley-Interscience. The protecting group may also be a polymer resinsuch as a Wang resin or a 2-chlorotrityl chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of the invention, as described abovein the Summary of the Invention, may not possess pharmacologicalactivity as such, they may be administered to a mammal having adisease-state characterized by thrombotic activity and thereaftermetabolized in the body to form compounds of the invention which arepharmacologically active. Such derivatives may therefore be described as“prodrugs”. All prodrugs of compounds of the invention are includedwithin the scope of the invention.

Accordingly, compounds of the invention as set forth in the Summary ofthe Invention may be prepared by methods disclosed in the literature,herein and/or as summarized in the following Reaction Schemes. Thefollowing Preparations (intermediates, made) and Examples (compounds ofthe invention, pharmaceutical compositions comprising the compounds andassays demonstrating their utility) are put forth so as to provide thoseof ordinary skill in the art with a complete disclosure and descriptionof how to make and use the subject invention, and are not intended tolimit the scope of what is regarded as the invention. Efforts have beenmade to ensure accuracy with respect to the numbers used (e.g. amounts,temperature, concentrations, etc.) but some experimental errors anddeviations should be allowed for. Unless otherwise indicated, parts areparts by weight, molecular weight is average molecular weight,temperature is in degrees centigrade; and pressure is at or nearatmospheric.

Compounds of formula (I), formula (Ia) and formula (Ib) are prepared asillustrated below in Reaction Scheme 1 wherein n is 0 to 5, and R¹, R²,and R⁵ are as described above in the Summary of the Invention,preferably where R¹ and R² are hydrogen or alkyl; and R³ and R⁴ are each—NH₂:

Compounds of formula (A), formula (C) and formula (E) are commerciallyavailable, for example, from Aldrich Chemical Co., or may be preparedaccording to methods known to one of ordinary skill in the art, or bythe methods disclosed herein in the Preparations.

In general, compounds of the invention are prepared by first diazotizinga primary amine of formula (A) by treatment with hydrochloric acid andsodium nitrite. The intermediate diazo compound of formula (B) is thentreated, in the presence of a base, for example, sodium acetate, with acompound of formula (C), i.e., a compound including a methylene groupflanked by the electron withdrawing cyano groups, to provide a compoundof formula (D). The compound of formula (D) is then reacted with ahydrazine compound of formula (E) to provide compounds of the invention.

The following Preparation and Examples exemplify the above ReactionScheme 1 in more detail.

Preparation 1 Preparation of Pyridinyl-3-amines

A. A solution of 2-chloro-5-nitropyridine (1.58 g, 10 mmol) andappropriate amine (20 mmol) in THF (60 mL) was heated for several hoursat 60° C. The solvent was evaporated and water was then added to thereaction mixture. The product was isolated by filtration (piperidine,morpholine), or extracted from the water solution with ethyl acetate(1-methylpiperazine, 2-(2-hydroxyethylamino)ethanol)).

B. To a solution of substituted nitropyridine (1 mmol) in THF:ethanolmixture (1:1) (50 mL) was added a catalytical amount of Raney-Nickel andhydrazine hydrate (4 mmol) and the mixture was stirred for 15 minutes atambient temperature, filtered through a Celite pad and the filtrate wasevaporated to provide the crude amine in very high yield. All amineswere used in further reactions without purification.

C. The following pyrdin-3-ylamines were prepared by the method describedabove:

-   6-(piperidin-1-yl)pyridin-3-ylamine;-   6-(morpholin-4-yl)pyridin-3-ylamine;-   6-(4-methylpiperazin-1-yl)pyridin-3-ylamine; and-   6-[di-(2-hydroxyethyl)amino]pyridin-3-ylamine.

Preparation 2 Preparation of 3-(Morpholin-4-yl)methylphenylamine

A. A solution of 1-bromomethyl-3-nitrobenzene (2.16 g, 10 mmol),morpholine (1.76 g, 20.2 mmol) and triethylamine (1.0 mL) in THF (60 mL)was heated for two hours at 60° C. The solvent was evaporated and waterwas then added to the reaction mixture. The product was isolated byextraction with ether. The ether layer was dried over anhydrous Mg₂SO₄and the solvent was evaporated. The crystalline residue was used infurther reactions without further purification. The yield of4-(3-nitrobenzyl)morpholine was 94% (2.09 g).

B. To a solution of 4-(3-nitrobenzyl)morpholine (2.0 g; 9.0 mmol) inTHF/ethanol mixture (1:1) (50 mL) was added a catalytical amount ofRaney-Nickel and hydrazine hydrate (36.0 mmol) and the mixture wasstirred at ambient temperature for 15 minutes, then filtered through aCelite-pad and the filtrate was evaporated to provide pure3-(morpholin-4-yl)methylphenylamine (2.03 g, 98%), which was used infurther reactions without purification.

Preparation 3 Preparation of 3-(Piperidin-1-yl)methylphenylamine

A. A solution of 1-bromomethyl-3-nitrobenzene (2.16 g, 10 mmol),piperidine (1.70 g, 20.2 mmol) and triethylamine (1.0 mL) in THF (60 mL)was heated for two hours at 60° C. The solvent was evaporated and waterwas then added to the reaction mixture. The product was isolated byextraction with ether. The ether extract was dried over anhydrous Mg₂SO₄and the solvent was evaporated. The crystalline residue obtained wasused in the next step without further purification. The yield of1-(3-nitrobenzyl)piperidine was 91% (2.01 g).

B. To a solution of 1-(3-nitrobenzyl)piperidine (263 mg; 1.19 mmol) inTHF:ethanol mixture (1:1) (15 mL) was added a catalytical amount ofRaney-Nickel and hydrazine hydrate (6.0 mmol) and the mixture wasstirred for 15 minutes at ambient temperature, filtered through aCelite-pad and the filtrate was evaporated to provide the title compound(180 mg, 95%), which was used in futher reactions without purification.

Preparation 4 Preparation of3-fluoro-4-(morpholin-4-yl)methylphenylamine

A. 2-Fluoro-4-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82g, 10 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved inCCl₄ (50 mL). The mixture was heated at reflux, and irradiated withlight (100 W bulb) for 4 hours. The reaction mixture was then filteredand concentrated. The residue was dissolved in THF (50 mL). Morpholine(1.91 g, 22 mmol) was added to it. The mixture was stirred at ambienttemperature for 1 hour and then filtered. The filtrate was evaporated.The bright orange residue was purified by column chromatography elutedwith hexane:ethyl acetate, 10:1 to provide4-(2-fluoro-4-nitrobenzyl)morpholine (1.32 g, 5.5 mmol, yield 55%).

B. To a solution of 4-(2-fluoro-4-nitrobenzyl)morpholine (240 mg, 1.0mmol) in THF/ethanol mixture (1:1) (25 mL) was added a catalyticalamount of Raney-Ni and hydrazine hydrate (9.0 mmol) and the mixture wasstirred at ambient temperature for 15 minutes, filtered through a Celitepad. The filtrate was evaporated to provide the title compound, (197 mg,94%), which was used in further reactions without purification.

Preparation 5 Preparation of N-Methyl-3-nitrobenzenesulfonamide andN-Methyl-4-nitrobenzenesulfonamide

To a solution of 1.326 g (6.0 mmol) of 3-nitrobenzenesulfonyl chlorideor 4-nitrobenzenesulfonyl chloride in 30 mL of dry THF was added 1.37 g(13.5 mmol) of triethylamine and then 4.0 mL (8.0 mmol) of methylamineas a solution in THF at 0° C. with stirring. The resulting cloudysolution was stirred overnight at ambient temperature. After this timeperiod, the reaction mixture was diluted with 100 mL of saturated sodiumchloride solution and 50 mL of ethyl acetate, then transferred to a 500mL separatory funnel, mixed thoroughly, and the organic phase wasseparated. The aqueous phase was extracted twice with 50 mL of ethylacetate. The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure, and the resultingresidue purified by recrystallization from EtOH. The yield ofN-methyl-3-nitrobenzenesulfonamide was 83% (1.074 g) and 90% forN-methyl-4-nitrobenzenesulfonamide (1.17 g).

Preparation 6 Preparation of N-Ethyl-3-nitrobenzenesulfonamide andN-Ethyl-4-nitrobenzenesulfonamide

To a suspension of 0.7 g (3.16 mmol) of 3-nitrobenzenesulfonyl chlorideor 4-nitrobenzenesulfonyl chloride in 10 mL of water was addedethylamine (5.0 ml, 70% in water) with stirring. The resulting solutionwas stirred overnight at ambient temperature. After this time period,the reaction mixture was diluted with 20 mL of saturated sodium chloridesolution and 50 mL of ether, then transferred to a separatory funnel,mixed thoroughly, and the organic phase was separated. The aqueous phasewas extracted twice with 50 mL of ether. The combined organic layerswere washed with 10% hydrochloric acid, dried over Na₂SO₄, concentratedunder reduced pressure, and the resulting residue was purified byrecrystallization from EtOH. The yield ofN-ethyl-3-nitrobenzenesulfonamide was 85% (0.618 g, 2.69 mmol) and 84%for N-ethyl-4-nitrobenzenesulfonamide (0.648 g, 2.82 mmol).

Preparation 7 Preparation of 3-Amino-5-nitrobenzoic acid ethyl ester

3-Amino-5-nitrobenzoic acid (910 mg, 5.0 mmol) was dissolved in EtOH (25mL). DCC (1.51 g, 7.3 mmol) was added, and the mixture was stirred underreflux overnight. The solid precipitation was filtered off and thefiltrate was evaporated. The residue was triturated in the solventmixture ether:hexane:ethyl acetate, 5:5:1. The title compound wasisolated as a fine light yellow powder (0.9 g, 85.7%).

Preparation 8 Preparation ofMorpholin-4-yl-(3-nitro-5-(trifluoromethyl)phenyl)methanone

To a solution of 3-nitro-5-(trifluoromethyl)benzoic acid (470 mg, 2mmol) in methylene chloride (10 mL) was added thionyl chloride (2.0 mL)and one drop of DMF under stirring and ice-cooling. The solution wasstirred at ambient temperature for 2 hours. All solvents were evaporatedand the residue was dissolved in THF (15 mL). The mixture was cooled to0° C. and morpholine (180 mg) was added. The cloudy solution was stirredat ambient temperature overnight, filtered off and evaporated. Theresidue was mixed with 5% HCl solution and extracted with ether. Theether layer was washed with NaOH solution, dried over anhydrous Na₂SO₄and evaporated to dryness to affordmorpholin-4-yl-(3-nitro-5-(trifluoromethyl)phenyl)methanone (545 mg,1.79 mmol, 89%).

Preparation 9 Preparation of 4-(5-Fluoro-2-nitrobenzyl)morpholine

5-Fluoro-2-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82 g,10 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved in CCl₄(50 mL), heated at reflux, and irradiated with light (100 W bulb) for 4hours. The reaction mixture was filtered and concentrated. The residuewas dissolved in THF (50 mL). Morpholine (1.9 g, 22 mmol) was added tothe THF solution. The mixture was stirred at ambient temperature for 1hour and then filtered. The solvent of the filtrate was evaporated. Thebright orange residue obtained was then mixed with 5% HCl solution (30mL) and extracted with ethyl acetate (2×25 mL). The aqueous layer wasbasified with NaOH solution to pH 8 and then extracted with methylenechloride. Both ethyl acetate solution and methylene chloride solutionwere dried over anhydrous Na₂SO₄ separately. Evaporation of ethylacetate solution afforded an orange oil which was recrystallized fromhexane:ether solution to yield 450 mg of a yellow solid,4-(3-methyl-4-nitrophenyl)morpholine (18%), the by-product. Evaporationof methylene chloride solution afforded 660 mg of the desired compound,4-(5-fluoro-2-nitrobenzyl)morpholine (27.5%).

Preparation 10 Preparation of4-(3-Nitro-5-trifluoromethylbenzyl)morpholine

To a solution ofmorpholin-4-yl-(3-nitro-5-(trifluoromethyl)phenyl)methanone (304 mg, 1.0mmol) in 15 mL of THF was added lithium aluminum hydride (152 mg, 4mmol) in THF (7 mL) under nitrogen. The dark colored solution wasrefluxed for 2 hours and then cooled. NaOH solution was added (0.5 N, 15mL) dropwise. The basic solution was washed with methylene chloride(3×40 mL) and the pooled organic layers were washed with HCl solution(5%). The aqueous layer was separated, basified with NaOH to pH 8, andextracted with ethyl acetate. The ethyl acetate solution was dried overanhydrous Na₂SO₄. The solution was used in further reactions withoutfurther work-up.

Preparation 11 Preparation of 4-Fluoro-2-morpholin-4-ylmethylphenylamine

To a solution of 4-(5-fluoro-2-nitrobenzyl)morpholine (240 mg; 1.0 mmol)in THF:ethanol mixture (1:1) (40 mL) was added a catalytical amount ofRaney-Nickel and hydrazine hydrate (6.0 mmol). The mixture was stirredfor 30 minutes at ambient temperature, then filtered through a Celitepad and the filtrate was evaporated to provide the title compound (208mg, 99%), which was used in further reactions without purification.

Preparation 12 Preparation of 3-Fluoro-4-morpholin-4-ylmethylphenylamine

2-Fluoro-4-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82 g,10 mmol),

-   and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved in CCl₄ (50    mL). The mixture was heated at reflux, and irradiated with light    (100 W bulb) for 4 hours. The reaction mixture was filtered and    concentrated. The residue was dissolved in THF (50 mL) and    morpholine (1.9 g, 22 mmol) was added to this solution. The mixture    was stirred at ambient temperature for 1 hour, and then filtered.    The filtrate was evaporated. The title compound was isolated by    column chromatography in an amount of 710 mg (30% yield).

Preparation 13 Preparation of3-fluoro-4-(morpholin-4-yl)methylphenylamine

To a solution of 4-(2-fluoro-4-nitrobenzyl)morpholine (245 mg; 1.02mmol) in THF:ethanol mixture (1:1) (40 mL) was added a catalyticalamount of Raney-Nickel and hydrazine hydrate (6.0 mmol) and the mixturewas stirred for 20 minutes at ambient temperature, then filtered througha Celite/silica gel pad. The filtrate was evaporated to provide thetitle compound (210 mg, 99%), which was used in further reactionswithout purification.

Preparation 14 Preparation of3-(Morpholin-4-yl)methyl-5-trifluoromethylphenylamine

A. To a solution ofmorpholin-4-yl-(3-nitro-5-(trifluoromethyl)phenyl)methanone (457 mg, 1.5mmol) in THF (5 mL) was added dropwise a solution of boranetetrahydrofuran complex solution (3.1 mL, 3.1 mmol) at ambienttemperature and the mixture was heated under reflux for 30 minutes, thencooled. The solvent was evaporated. Aqueous HCl (5 mL) was added and theresulting mixture was heated at 100° C. for 1 hour, then cooled andextracted with ether. The acidic aqueous layer was separated, basifiedto pH 8 with NaOH and extracted with ether. The ether solution was driedover anhydrous Na₂SO₄. Evaporation of ether provided 168 mg (0.57 mmol)of 4-(3-Nitro-5-trifluoromethylbenzyl)morpholine (38%).

B. To a solution of 4-(3-nitro-5-trifluoromethylbenzyl)morpholine (168mg; 0.57 mmol) in THF:ethanol mixture (1:1) (30 mL) was added acatalytical amount of Raney-Nickel and hydrazine hydrate (4.0 mmol) andthe mixture was stirred for 2 hours at ambient temperature, thenfiltered through a Celite/silical gel pad. The filtrate was evaporatedto provide the title compound (152 mg, 98%), which was used in furtherreactions without purification.

Preparation 15 Preparation of (3-Amino-5-nitrophenyl)methanol

To a solution of 3-amino-5-nitrobenzoic acid (1.12 g, 6.16 mmol) in THF(5 mL) was added dropwise a solution of borane tetrahydrofuran complexsolution (13.6 mL, 13.6 mmol) at ambient temperature and the mixture wasstirred for 90 minutes. The solvent was then evaporated. Aqueous NaOH(15 mL) was added and the resulting mixture was extracted with ether.The ether solution was dried over anhydrous Na₂SO₄. Evaporation of etherafforded 921 mg of the title compound (89%).

Preparation 16 Preparation of p- and m-methylphenylamines

A. A solution of 1-bromomethyl-3(or 4)-nitrobenzene (1 above) (n=1) (432mg; 2.0 mmol), an appropriate amine (a-d above) (4.1 mmol) andtriethylamine (0.3 mL) in THF (15 mL) was heated for 2 hour at 60° C.The solvent was evaporated. Water was added to the residue and theproduct was isolated by extraction with ether (3×20 mL). The etherextract was dried over anhydrous MgSO₄ and the solvent was removed. Theresidue was used in the next step without further purification. Theyield of compounds (2a-d above) ranged from 81-99%.

B. To a solution of compounds 2a-d above (1.0 mmol) in THF:ethanolmixture (1:1) (15 mL) was added a catalytical amount of Raney-Nickel andhydrazine hydrate (4.0 mmol) and the mixture was stirred for 30-60minutes at ambient temperature, then filtered through a Celite/silicagel pad. The filtrate was evaporated to provide pure compounds 3a-dabove in almost quantitative yield, which were used in further reactionswithout purification.

Preparation 17 Preparation of 4-[2-(4-Nitrophenyl)ethyl]morpholine

To a solution of 1-(2-bromoethyl)-4-nitrobenzene (460 mg, 2.0 mmol) inacetone (15 mL) was added morpholine (610 mg, 7.0 mmol) and 680 mg ofK₂CO₃. The mixture was stirred for 80 hours at ambient temperature, andthen poured into water. The aqueous mixture was extracted with ether.The organic layer was washed with brine, dried over MgSO₄, andevaporated in vacuo to give 456 mg (1.93 mmol; 97%) of the titlecompound, which was converted to the appropriate amine by the methoddisclosed in Preparation 16.

Preparation 18 Preparation of1-[2-(2-Methoxyethoxy)ethoxymethyl]-3-nitrobenzene

To a solution of 1-bromomethyl-3-nitrobenzene (2 mmol; 432 mg) indi(ethylene glycol)methyl ether (15 mL) was added KOH powder (0.5 g) andthe solution was stirred at ambient temperature overnight. Water (70 mL)was added and the product extracted with ether. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated in vacuum to provide thetitle compound (342 mg, 1.52 mmol, 67% yield), which was converted tothe appropriate amine by method disclosed in Preparation 16.

Preparation 19 Preparation of N-methyl-3-nitrobenzenesulfonamide

To a solution of 4.42 g (20.0 mmol) of 3-nitrobenzenesulfonyl chloridein 150 mL of dry THF was added 25.0 mL (50.0 mmol) of methylamine as a 2M solution in THF under ice cooling and stirring. The resulting cloudysolution was stirred overnight at ambient temperature. After this timeperiod, the reaction mixture was diluted with 150 mL of saturated sodiumchloride solution and 50 mL of ethyl acetate, then transferred to a 500mL separatory funnel, mixed thoroughly, and the organic phase wasseparated. The aqueous phase was extracted twice with 50 mL of ethylacetate. The combined organic layers were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The resulting residue waspurified by recrytallization from EtOH. The yield of the title compoundwas 97% (4.20 g, 19.48 mmol).

Preparation 20 Preparation of3-(Morpholin-4-yl)methyl-5-nitrophenylamine

A. A solution of (3-amino-5-nitrophenyl)methanol (872.5 mg; 5.14 mmol)in 7 mL of anhydrous hydrogen bromide in glacial acetic acid wasrefluxed for 8 hours. The solution was cooled to about 20° C. and thenmixed with 5% NaOH (30 mL) solution and extracted with ether. Organiclayer was separated, dried over MgSO₄ and concentrated in vacuo to yielda yellow solid (889 mg), which was purified by column chromatography.The light yellow crystals, 3-bromomethyl-5-nitrophenylamine, wereisolated in an amount of 490 mg (2.12 mmol, 41%); MS (m/z, ES+): 231(M+1 (⁷⁹Br)), 233 (M+1 (⁸¹Br), 100%).

B. A solution of 3-bromomethyl-5-nitrophenylamine (398 mg, 1.72 mmol),triethylamine (0.3 mL) and morpholine (0.2 mL) in 15 mL of THF washeated at 60° C. for 30 minutes. The solvent was evaporated in vacuo.The residue was mixed with water (20 mL) and extracted with ether.Organic layer was separated, dried over MgSO₄ and concentrated in vacuoto afford a yellow solid (411 mg), which was purified by columnchromatography. The title compound was isolated as yellow crystals in anamount of 302 mg (1.274 mmol, 74%); MS (m/z, ES+): 238 (M+1, 100%).

Example 1 Preparation of4-[(4-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine

A. To a flask containing p-anisidine (5.46 g, 44.3 mmol) andconcentrated HCl solution (11 mL) in 75 mL of water, cooled in an icewater bath, was added sodium nitrite solution (4.57 g, 66.3 mmol). Theresulting mixture was then added to a solution of malononitrile (4.79 g,72.6 mmol) in a mixture of methanol (MeOH) (12 mL) and water (25 mL). Alarge quantity of yellow solid quickly precipitated. The mixture wasstirred for about 30 minutes at ambient temperature. The solid wascollected and purified by recrystallization in hot ethanol. The product(6.17 g, 70%) was obtained as a yellow solid.

B. To a suspension of the yellow solid (2.00 g) prepared above in 10 mLof ethanol was added hydrazine hydrate (2.0 mL). This mixture wasrefluxed for about 3 hours. The yellow solid was collected and purifiedby recrystallization in hot ethanol (EtOH). The product,4-[(4-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine, was isolated asyellow cotton-like solid (1.50 g, 65%); m.p. 263-265° C.; ¹H NMR (ppm,in DMSO-d₆): 10.73 (s, br, 1H), 7.69 (m, 2H), 6.99 (m, 2H), 6.00 (s, br,4H), 3.81 (s, 3H); ¹³C NMR (ppm, in DMSO-d₆): 158.4, 147.6, 121.7,114.0, 113.4, 99.9, 55.3; FTIR (cm⁻¹, KBr pellet): 3401, 3301, 3187,1603, 562, 1498, 1248, 1033, 828; Mass spectrometry (m/e, EI): 232 (M⁺,100%); Elemental analysis for C₁₀H₁₂N₆O (obtained/calcd.): C,52.28/51.72, H, 5.18/5.21, N, 35.88/36.19; Molecular Weight (MW):232.24.

C. In a similar manner as described above in Paragraph A and B, thefollowing compounds were synthesized:

-   4-(phenylhydrazono)-4H-pyrazole-3,5-diamine, MW 202.21-   4-(p-tolylhydrazono)-4H-pyrazole-3,5-diamine, MW 216.24;-   5-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-methoxyphenol, MW    248.24;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonic acid,    MW 282.27;-   4-(morpholin-4-ylhydrazono)-4H-pyrazole-3,5-diamine, MW 211.22;-   4-[(2-(morpholin-4-yl)ethyl)hydrazono]-4H-pyrazole-3,5-diamine, MW    239.28;-   4-[(1H-imidazol-2-yl)hydrazono]-4H-pyrazole-3,5-diamine, MW 192.18;-   4-[(1H-pyrazol-3-yl)-hydrazono]-4H-pyrazole-3,5-diamine, MW 192.18;-   4-(thiazol-2-ylhydrazono)-4H-pyrazole-3,5-diamine, MW 209.22;-   4-(naphthalen-1-ylhydrazono)-4H-pyrazole-3,5-diamine, MW 252.27;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]naphthalene-1-sulfonic    acid, MW 332.33;-   4-(piperidin-4-ylmethylhydrazono)-4H-pyrazole-3,5-diamine, MW    223.28;-   4-(1,2,4-triazin-3-ylhydrazono)-4H-pyrazole-3,5-diamine, MW 205.18;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzoic acid, MW    246.22;-   4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenol, MW 218.21;-   4-[(4-chlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine, MW 236.66;-   4-[(4-butylphenyl)hydrazono]-4H-pyrazole-3,5-diamine, MW 258.32;-   N-{4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}acetamide,    MW 274.3;-   1-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]naphthalen-2-ol, MW    268.27.

Example 2 Preparation of Compounds of Formula (I), formula (Ia) andformula (Ib)

A. 4-Fluoroaniline (95 μL, 1.0 mmol) was weighed into a 25 mL test tube.Deionized water (1-2 mL) was added to the test tube and the suspensionwas cooled to below 5° C. in an ice bath. Concentrated HCl (250 μL, 3.0mmol) was added dropwise to the mixture. If the solution remainedinhomogeneous, dimethylformamide (DMF) was added until all the solidshad dissolved (0-2 mL). An aqueous sodium nitrite solution (290 μL of a5.25 M solution, 1.5 mmol) was added dropwise to this mixture andallowed to stir for approximately 5 minutes. The resulting clear paleyellow solution was then added dropwise to a second 25 mL test tubecontaining 1.4 mL of an ice cold aqueous solution which was 1.82 M (2.3mmol) in sodium acetate trihydrate and 1.09 M (1.5 mmol) inmalononitrile. A precipitate formed immediately. The reaction solutionwas stirred for 1-2 hrs while warming to ambient temperature. Thesolution was then filtered and the precipitate was washed twice with 5mL of deionized water. The product was dried overnight under vacuum toyield 169 mg (90%) of the desired malononitrile derivative as a yellowsolid. A portion of this solid (94 mg, 0.5 mmol) was weighed into a 25mL test tube. Anhydrous ethanol (1.5 mL) was added and the slurry washeated to 75° C. Once the solid had dissolved, hydrazine hydrate (1mmol) was added dropwise via micropipette. A precipitate usually formedwithin 10 minutes. The reaction was monitored for the disappearance ofthe starting material by thin layer chromatography (TLC). Once thereaction was complete, the solution was allowed to cool to ambienttemperature. The solid was isolated by filtration, washed with ethanol,and dried to yield 17 mg (15%) of4-[(4-fluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine as a mustardcoloured solid.

B. In a similar manner, the following compounds were prepared:

1. 3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenol was preparedusing 93 mg (0.5 mmol) of 2-[(3-hydroxyphenyl)-hydrazono]malononitrile,which was derived from 3-aminophenol (109 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. After heating for 4hrs, a small amount of solid had formed. The solid was filtered off andthe filtrate was concentrated to a gummy black solid. This material wasdissolved in ethyl acetate and a small amount of gummy solid wasprecipitated from the solution by the addition of hexanes. The solid wasremoved by filtration and the filtrate was again concentrated. Theresulting solid was purified by flash chromatography eluting withmethylene chloride/methanol (7:1) to yield 45 mg (33%) of the compoundas a black solid.

2. 4-[(3-ethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 99 mg (0.5 mmol) of 2-[(3-ethylphenyl)hydrazono]malononitrile,which was derived from 3-ethylaniline (124 μL, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed inthe reaction tube approximately 10 minutes after the addition ofhydrazine hydrate. The resulting solid was isolated by filtration,precipitated from an ethyl acetate solution by the addition of hexanes,and dried to yield 12 mg (10%) of the compound as a yellow solid.

3. 4-[(3-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 100 mg (0.5 mmol) of 2-[(3-methoxyphenyl)hydrazono]malononitrile,which was derived from m-anisidine (112 μL, 1.0 mmol) and malononitrile(1.5 mmol), and hydrazine hydrate. Precipitate formed in the reactiontube approximately 10 minutes after the addition of hydrazine hydrate.The resulting solid was isolated by filtration, recrystallized fromethanol, and dried to yield 25 mg (22%) of the compound as a brownishorange solid.

4. 4-[(3-chlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 102 mg (0.5 mmol) of 2-[(3-chlorophenyl)hydrazono]malononitrile,which was derived from 3-chloroaniline (106 μL, 1.0 mmol) andmalononitrile (1.5 mmol) as described in Example 2, and hydrazinehydrate. Precipitate formed in the reaction tube approximately 5 minafter the addition of hydrazine hydrate. The resulting solid wasisolated by filtration, precipitated from an ethyl acetate solution bythe addition of hexanes, and dried to yield 17 mg (14%) of the compoundas a yellow solid; ¹H NMR (ppm, DMSO-d₆): 5.98 (br, s, 2H), 6.38 (br, s,2H), 7.18 (d, 1H), 7.40 (t, 1H), 7.60 (d, 1H), 7.69 (s, 1H), 10.78 (s,1H).

5. 4-[(3-fluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 94 mg (0.5 mmol) of 2-[(3-fluorophenyl)hydrazono]malononitrile,which was derived from 3-fluoroaniline (96 μL, 1.0 mmol) andmalononitrile (1.5 mmol) and hydrazine hydrate. Precipitate formed inthe reaction tube approximately 5 minutes after the addition ofhydrazine hydrate. The resulting solid was isolated by filtration,washed with ethanol, and dried to yield 41 mg (37%) of the compound as ayellow solid. ¹H NMR (ppm, DMSO-d₆): 6.2 (br s, 4H), 7.0 (t, 1H),7.35-7.62 (m, 3H), 10.80 (s, 1H).

6. 4-[(3-fluoro-4-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 109 mg (0.5 mmol) of2-[(3-fluoro-4-methoxyphenyl)hydrazono]malononitrile, which was derivedfrom 3-fluoro-p-anisidine (141 mg, 1.0 mmol) and malononitrile (1.5mmol), and hydrazine hydrate. Precipitate formed in the reaction tubeimmediately after the addition of hydrazine hydrate. The resulting solidwas isolated by filtration, washed with ethanol, and dried to yield 85mg (68%) of the compound as a mustard coloured solid.

7. 4-(naphthalen-2-ylhydrazono)-4H-pyrazole-3,5-diamine was preparedusing 110 mg (0.5 mmol) of 2-[(naphthalen-2-yl)hydrazono]malononitrile,which was derived from 2-aminonaphthalene (143 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydratewas added to the solution at a temperature of 75° C. despite the factthat the starting material had not fully dissolved. The solution clearedbriefly and then a precipitate formed. The resulting solid was isolatedby filtration, washed with ethanol, and dried to yield 86 mg (67%) ofthe compound as a tan coloured solid.

8. 4-[(4-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 119 mg (0.5 mmol) of2-[(4-trifluoromethylphenyl)hydrazono]malononitrile, which was derivedfrom 4-(trifluoromethyl)aniline (126 μL, 1.0 mmol) and malononitrile(1.5 mmol), and hydrazine hydrate. No precipitate had formed afterheating at 75° C. for 1 hr, however, analysis of the reaction solutionby TLC indicated that no starting material remained. The solution wasallowed to cool to ambient temperature and the solvent was evaporated.The residue was dissolved in ethyl acetate and then precipitated by theaddition of hexanes. The resulting solid was isolated by filtration anddried to yield 67 mg (50%) of the compound as a greenish brown solid; ¹HNMR (ppm, DMSO-d₆): 6.03 (br s, 2H), 6.48 (br s, 2H), 7.63 (d, 2H), 7.80(d, 2H), 10.80 (br s, 1H).

9. -[(3-phenoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 131 mg (0.5 mmol) of 2-[(3-phenoxyphenyl)hydrazono]malononitrile,which was derived from 3-phenoxyaniline (185 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed inthe reaction tube approximately 5 minutes after the addition ofhydrazine hydrate. The resulting solid was isolated by filtration,recrystallized from ethanol, and dried to yield 87 mg (59%) of thecompound as a mustard coloured solid.

10. 4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzoic acid ethylester was prepared using 121 mg (0.5 mmol) of4-(N′-dicyanomethylenehydrazino)benzoic acid ethyl ester, which wasderived from ethyl 4-aminobenzoate (165 mg, 1.0 mmol) and malononitrile(1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added tothe solution at a temperature of 75° C. The solution cleared briefly andthen a precipitate formed. The resulting solid was isolated byfiltration, washed with ethanol, and dried to yield 45 mg (33%) of thecompound as a yellow solid.

11. 4-(3-phenylphenylhydrazono)-4H-pyrazole-3,5-diamine was preparedusing 123 mg (0.5 mmol) of 2-[(biphenyl-2-yl)hydrazono]malononitrile,which was derived from 2-aminobiphenyl (169 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed inthe reaction tube immediately after the addition of the hydrazinehydrate then the solution cleared. Very little solid remained afterheating the reaction at 75° C. for 1 hr, however, analysis of thereaction solution by TLC indicated that no starting material remained.The solution was allowed to cool to ambient temperature and the solventwas evaporated. The residue was dissolved in ethyl acetate and thenprecipitated by the addition of hexanes. The resulting solid wasisolated by filtration and dried to yield 85 mg (61%) of the compound asan orange solid.

12. 4-[(2-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 125 mg (0.5 mmol) of 2-[(2-bromophenyl)hydrazono]malononitrile,which was derived from 2-bromoaniline (172 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. Very little solid hadformed after heating the reaction at 75° C. for 1 hr, however, analysisof the reaction solution by TLC indicated that no starting materialremained. The solution was allowed to cool to ambient temperature andthe solvent was evaporated. The residue was dissolved in ethyl acetateand then precipitated by the addition of hexanes. The resulting solidwas isolated by filtration and dried to yield 102 mg (73%) of thecompound as an orange solid.

13. 4-[(3-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 125 mg (0.5 mmol) of 2-[(3-bromophenyl)hydrazono]malononitrile,which was derived from 3-bromoaniline (172 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydratewas added to the solution at a temperature of 75° C. despite the factthat the starting material had not fully dissolved. The solution clearedbriefly and then a precipitate formed. The resulting solid was isolatedby filtration, washed with ethanol, and dried to yield 93 mg (66%) ofthe compound as an orange solid; ¹H NMR (ppm, DMSO-d₆): 6.2 (br s, 4H),7.21-7.32 (m, 2H), 7.50-7.62 (m, 1H), 7.90 (s, 1H), 10.71 (s, 1H).

14. 4-[(4-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 125 mg (0.5 mmol) of 2-[(4-bromophenyl)hydrazono]malononitrile,which was derived from 4-bromoaniline (172 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydratewas added to the solution at a temperature of 75° C. despite the factthat the starting material had not fully dissolved. The solution clearedbriefly and then a precipitate formed. The resulting solid was isolatedby filtration, washed with ethanol, and dried to yield 109 mg (78%) ofthe compound as a yellow solid; ¹HNMR (ppm, DMSO-d₆): 6.15 (brs, 4H),7.52 (d, 2H), 7.61 (d, 2H), 10.71 (s, 1H).

15. 4-[(4-phenoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 131 mg (0.5 mmol) of 2-[(4-phenoxyphenyl)hydrazono]malononitrile,which was derived from 4-phenoxyaniline (185 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydratewas added to the solution at a temperature of 75° C. despite the factthat the starting material had not fully dissolved. The solution clearedbriefly and then a precipitate formed. The resulting solid was isolatedby filtration, washed with ethanol, and dried to yield 90 mg (61%) ofthe compound as an orange solid.

16. 4-[(4-iodophenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 148 mg (0.5 mmol) of 2-[(4-iodophenyl)hydrazono]malononitrile,which was derived from 4-iodoaniline (219 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydratewas added to the solution at a temperature of 75° C. despite the factthat the starting material had not fully dissolved. The solution clearedbriefly and then a precipitate formed. The resulting solid was isolatedby filtration, washed with ethanol, and dried to yield 114 mg (70%) ofthe compound as a yellow solid.

17. 4-[(4-bromonaphthalen-1-yl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 149 mg (0.5 mmol) of2-[(4-bomonaphthalen-1-yl)hydrazono]malononitrile, which was derivedfrom 1-amino-4-bromonaphthalene (222 mg, 1.0 mmol) and malononitrile(1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added tothe solution at a temperature of 75° C. despite the fact that thestarting material had not fully dissolved. The solution cleared. Verylittle solid had formed after heating the reaction at 75° C. for 1 hr,however, analysis of the reaction solution by TLC indicated that nostarting material remained. The solution was allowed to cool to ambienttemperature and the solvent was evaporated. The residue was dissolved inmethanol and then precipitated by the addition of water. The resultingsolid was isolated by filtration and dried to yield 42 mg (26%) of thecompound as a brown solid.

18. 4-(o-tolylhydrazono)-4H-pyrazole-3,5-diamine was prepared using 92mg (0.5 mmol) of 2-(o-tolylhydrazono)-malononitrile, which was derivedfrom 4-toluidine (107 μL, 1.0 mmol) and malononitrile (1.5 mmol), andhydrazine hydrate. Very little solid had formed after heating thereaction at 75° C. for 1 hr, however, analysis of the reaction solutionby TLC indicated that no starting material remained. The solution wasallowed to cool to ambient temperature and the solvent was evaporated.The residue was dissolved in ethyl acetate and then precipitated by theaddition of hexanes. The resulting solid was isolated by filtration anddried to yield 43 mg (40%) of the compound as a yellow solid.

19. 4-[(2,6-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 103 mg (0.5 mmol) of2-[(2,6-difluorophenyl)hydrazono]malononitrile, which was derived from2,6-difluoroaniline (108 μL, 1.0 mmol) and malononitrile (1.5 mmol), andhydrazine hydrate. Precipitate formed in the reaction tube approximately10 minutes after the addition of hydrazine hydrate. The resulting solidwas isolated by filtration, washed with ethanol, and dried to yield 44mg (37%) of the compound as an orange solid.

20. 4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 103 mg (0.5 mmol) of2-[(3,4-difluorophenyl)hydrazono]malononitrile, which was derived from3,4-difluoroaniline (99 μL, 1.0 mmol) and malononitrile (1.5 mmol), andhydrazine hydrate. Precipitate formed in the reaction tube approximately5 minutes after the addition of hydrazine hydrate. The resulting solidwas isolated by filtration, washed with ethanol, and dried to yield 45mg (38%) of the compound as a yellow solid; ¹H NMR (ppm, DMSO-d₆): 6.18(br s, 4H), 7.28-7.55 (m, 2H), 7.70-7.82 (m, 1H), 10.80 (br s, 1H).

21. 4-(benzo[1,3]dioxol-5-ylhydrazono)-4H-pyrazole-3,5-diamine wasprepared using 107 mg (0.5 mmol) of2-(benzo[1,3]dioxol-5-yl-hydrazono)malononitrile, which was derived from3,4-methylenedioxyaniline (137 mg, 1.0 mmol) and malononitrile (1.5mmol), and hydrazine hydrate. Precipitate formed in the reaction tubeapproximately 10 minutes after the addition of hydrazine hydrate. Theresulting black solid was isolated by filtration, dissolved in acetone,and hexanes was added to precipitate a small amount of black solid. Thesolid was removed by filtration and the filtrate was concentrated toyield 1.0 mg (1% yield) of the compound as a black solid; ¹H NMR (200MHz, DMSO-d₆) δ: 6.0 (br s, 6H), 6.92 (d, 1H), 7.18 (d, 1H), 7.38 (s,1H), 10.60 (br s, 1H).

22. 4-[(4-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 108 mg (0.5 mmol) of2-[(4-methylsulfanylphenyl)hydrazono]malononitrile, which was derivedfrom 4-methylthioaniline (117 mg, 1.0 mmol) and malononitrile (1.5mmol), and hydrazine hydrate. Precipitate formed in the reaction tubeimmediately after the addition of hydrazine hydrate. The resulting solidwas isolated by filtration, washed with ethanol, and dried to yield 95mg (77%) of the compound as an orange solid.

23.4-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared using 114 mg (0.5 mmol) of2-[(2,3-dihydro-benzo[1,4]dioxin-6-yl)hydrazono]malononitrile, which wasderived from 1,4-benzodiozan-6-amine (151 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydratewas added to the solution at a temperature of 75° C. despite the factthat the starting material had not fully dissolved. The solutioncleared. Very little solid had formed after heating the reaction at 75°C. for 1 hr, however, analysis of the reaction solution by TLC indicatedthat no starting material remained. The solution was allowed to cool toambient temperature and the solvent was evaporated. The residue wasdissolved in ethyl acetate and then precipitated by the addition ofhexanes. The resulting solid was isolated by filtration and dried toyield 35 mg (27%) of the compound as a tan coloured solid.

24. 4-[(3-chloro-4-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 117 mg (0.5 mmol) of2-[(3-chloro-4-methoxyphenyl)hydrazono]malononitrile, which was derivedfrom 3-chloro-4-anisidine (157 mg, 1.0 mmol) and malononitrile (1.5mmol), and hydrazine hydrate. Precipitate formed in the reaction tubeimmediately after the addition of hydrazine hydrate. The resulting solidwas isolated by filtration, washed with ethanol, and dried to yield 93mg (70%) of the compound as a yellow solid.

25. 4-[(3,4-dichlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 120 mg (0.5 mmol) of2-[(3,4-dichlorophenyl)hydrazono]malononitrile, which was derived from3,4-dichloroaniline (162 mg, 1.0 mmol) and malononitrile (1.5 mmol), andhydrazine hydrate. Precipitate formed in the reaction tube immediatelyafter the addition of hydrazine hydrate. The resulting solid wasisolated by filtration, precipitated from an ethyl acetate solution bythe addition of hexanes, and dried to yield 53 mg (39%) of the compoundas a yellow solid; ¹H NMR (ppm, DMSO-d₆): 6.30 (br, s, 4H), 7.55-7.79(m, 2H), 7.95 (s, 1H), 10.80 (s, 1H).

26. 4-[(3,5-dichlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 120 mg (0.5 mmol) of2-[(3,5-dichlorophenyl)hydrazono]malononitrile, which was derived from3,5-dichloroaniline (162 mg, 1.0 mmol) and malononitrile (1.5 mmol), andhydrazine hydrate. Precipitate formed in the reaction tube approximately5 minutes after the addition of hydrazine hydrate. The resulting solidwas isolated by filtration, precipitated from an ethyl acetate solutionby the addition of hexanes, and dried to yield 25 mg (18%) of thecompound as a yellow solid.

27. 4-[(2-isopropylphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 106 mg (0.5 mmol) of2-[(2-isopropylphenyl)hydrazono]malononitrile, which was derived from2-isopropylaniline (142 μL, 1.0 mmol) and malononitrile (1.5 mmol), andhydrazine hydrate. Precipitate formed in the reaction tube approximately5 minutes after the addition of hydrazine hydrate. The resulting solidwas isolated by filtration, washed with ethanol, and dried to yield 90mg (73%) of the compound as a greenish yellow solid.

28. 4-[(3,4-dimethoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 115 mg (0.5 mmol) of2-[(3,4-dimethoxyphenyl)hydrazono]malononitrile, which was derived from4-aminoveratrole (153 mg, 1.0 mmol) and malononitrile (1.5 mmol), andhydrazine hydrate. The hydrazine hydrate was added to the solution at atemperature of 75° C. despite the fact that the starting material hadnot fully dissolved. The solution cleared. Very little solid had formedafter heating the reaction at 75° C. for 1 hr, however, analysis of thereaction solution by TLC indicated that no starting material remained.The solution was allowed to cool to ambient temperature and the solventwas evaporated. The residue was dissolved in ethyl acetate and thenprecipitated by the addition of hexanes. The resulting solid wasisolated by filtration and dried to yield 46 mg (35%) of the compound asa mustard coloured solid.

29. 4-[(3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 119 mg (0.5 mmol) of2-[(3-trifluoromethylphenyl)hydrazono]malononitrile, which was derivedfrom 3-(trifluoromethyl)aniline (125 μL, 1.0 mmol) and malononitrile(1.5 mmol), and hydrazine hydrate. Precipitate formed in the reactiontube approximately 10 minutes after the addition of hydrazine hydrate.The resulting solid was isolated by filtration, washed with ethanol, anddried to yield 43 mg (31%) of the compound as a yellow solid.

30. 3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzoic acid ethylester was prepared using 121 mg (0.5 mmol) of3-(N′-dicyanomethylenehydrazino)benzoic acid ethyl ester, which wasderived from 3-aminobenzoate (149 μL, 1.0 mmol) and malononitrile (1.5mmol), and hydrazine hydrate. Precipitate formed in the reaction tubeapproximately 10 minutes after the addition of hydrazine hydrate. Theresulting solid was isolated by filtration, washed with ethanol, anddried to yield 58 mg (42%) of the compound as a light brown solid.

31.4-[(3-methoxy-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared using 134 mg (0.5 mmol) of2-[(3-methoxy-5-trifluoromethylphenyl)hydrazono]malononitrile, which wasderived from 3-methoxy-5-trifluoromethylaniline (191 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. Very little solid hadformed after heating the reaction at 75° C. for 1 hr, however, analysisof the reaction solution by TLC indicated that no starting materialremained. The solution was allowed to cool to ambient temperature andthe solvent was evaporated. The residue was dissolved in ethyl acetateand then precipitated by the addition of hexanes. The resulting solidwas isolated by filtration and dried to yield 10 mg (7%) of the compoundas a yellow solid.

32. 4-[(2-chlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 102 mg (0.5 mmol) of 2-[(2-chlorophenyl)hydrazono]malononitrile,which was derived from 2-chloroaniline (105 μL, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed inthe reaction tube approximately 10 minutes after the addition ofhydrazine hydrate. The resulting solid was isolated by filtration,washed with ethanol, and dried to yield 34 mg (29%) of the compound as ayellow solid.

33. 4-[(3-iodophenyl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 148 mg (0.5 mmol) of 2-[(3-iodophenyl)hydrazono]malononitrile,which was derived from 3-iodoaniline (219 mg, 1.0 mmol) andmalononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydratewas added to the solution at a temperature of 75° C. despite the factthat the starting material had not fully dissolved. The solution clearedbriefly and then a precipitate formed. The resulting solid was isolatedby filtration, washed with ethanol, and dried to yield 122 mg (74%) ofthe compound as a mustard coloured solid.

34. 4-[(9-ethyl-9H-carbazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 143 mg (0.5 mmol) of2-[(9-ethyl-9H-carbazol-3-yl)hydrazono]malononitrile, which was derivedfrom 3-amino-9-ethylcarbazole (210 mg, 1.0 mmol) and malononitrile (1.5mmol), and hydrazine hydrate. Solids had not formed after heating thereaction at 75° C. for 1 hr, however, analysis of the reaction solutionby TLC indicated that no starting material remained. The solution wasallowed to cool to ambient temperature and the solvent was evaporated.The residue was dissolved in ethyl acetate and then precipitated by theaddition of hexanes. The resulting solid was isolated by filtration anddried to yield 46 mg (29%) of the compound as a black solid.

35. 4-[(2-benzenesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using 94 mg (0.5 mmol) of2-[(2-benzenesulfonylphenyl)hydrazono]malononitrile, which was derivedfrom 2-(phenylsulfonyl)aniline (233 mg, 1.0 mmol) and malononitrile (1.5mmol), and hydrazine hydrate. Precipitate formed in the reaction tubeapproximately 20 minutes after the addition of hydrazine hydrate. Theresulting solid was isolated by filtration, washed with ethanol, anddried to yield 68 mg (20%) of the compound as an orange coloured solid.

36. 1-phenyl-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 200mg (1.2 mmol) of 2-(phenylhydrazono)malononitrile, which was derivedfrom aniline (10 mL, 107 mmol) and malononitrile (161 mmol), andphenylhydrazine (767 mg, 7.1 mmol). Solids had not formed after heatingthe reaction at 75° C. for 3 hrs, however, analysis of the reactionsolution by TLC indicated that no starting material remained. Thesolution was allowed to cool to ambient temperature and the solvent wasevaporated. The residue was dissolved in ethyl acetate and thenprecipitated by the addition of hexanes. The resulting solid wasisolated by filtration and dried to yield 77 mg (23%) of the compound asan orange coloured solid.

37. (3,5-diamino-4-phenylazopyrazol-1-yl)phenylmethanone was preparedusing 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which wasderived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), andbenzoic hydrazide (68 mg, 0.5 mmol). Solids had not formed after heatingthe reaction at 75° C. for 3 hrs, however, analysis of the reactionsolution by TLC indicated that no starting material remained. Thesolution was allowed to cool to ambient temperature and the solvent wasevaporated. The residue was dissolved in methanol and then precipitatedby the addition of water. The resulting solid was isolated by filtrationand dried to yield 20 mg (13%) of the compound as an orange colouredsolid.

38. 1-(4-bromophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine was preparedusing 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which wasderived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and4-bromophenylhydrazine hydrochloride (112 mg, 0.5 mmol) with theaddition of 0.5 mL of 5% sodium hydroxide solution. Solids had notformed after heating the reaction at 75° C. for 3 hrs, however, analysisof the reaction solution by TLC indicated that no starting materialremained. The solution was allowed to cool to ambient temperature andthe solvent was evaporated. The residue was dissolved in methanol andthen precipitated by the addition of water. The resulting solid wasisolated by filtration and dried to yield 49 mg (27%) of the compound asa brown solid.

39. 4-(3,5-diamino-4-phenylazopyrazol-1-yl)benzoic acid was preparedusing 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which wasderived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and4-hydrazinobenzoic acid (76 mg, 0.5° mmol). After reacting for 4 hrs,the reaction remained as a slurry; however, analysis of the reactionsolution by TLC indicated that no starting material remained. Theresulting solid was isolated by filtration, washed with ethanol, anddried to yield 22 mg (14%) of the compound as a brown solid.

40. 1-(4-fluorophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine was preparedusing 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which wasderived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and4-fluorophenylhydrazine hydrochloride (81 mg, 0.5 mmol) with theaddition of 0.5 mL of 5% sodium hydroxide solution. After reacting for 4hrs, very little solid had formed; however, analysis of the reactionsolution by TLC indicated that no starting material remained. Theresulting solid was removed by filtration and the solvent was evaporatedfrom the filtrate to yield 29 mg (20%) of the compound as a brown solid.

41. 4-(pyridin-3-ylhydrazono)-4H-pyrazole-3,5-diamine was prepared using2-[(pyridin-3-yl)hydrazono]malononitrile (342 mg, 2 mmol), which wasderived from 3-aminopyridine (940 mg, 10 mmol)) and malononitrile (858mg, 13 mmol), and hydrazine hydrate (110 mg, 2.2 mmol) in ethanol.Solids had not formed after heating the reaction at 80° C. for 40minutes, however, analysis of the reaction solution by TLC indicatedthat no starting material remained. The solution was allowed to cool toambient temperature and the solvent was evaporated. The product wasobtained after upon re-crystallization from ethanol as a yellow solid(150 mg); ¹H NMR (ppm, DMSO-d₆): 6.18 (br., s, 4H), 7.20 (dd, 1H), 8.00(dd, 1H), 8.38 (d, 1H), 8.85 (s, 1H), 10.77 (br., s, 1H).

42. 4-[(5-methoxybenzothiazol-2-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared using2-[(6-methoxybenzothiazol-2-yl)hydrazono]malononitrile (200 mg), whichwas derived from 2-amino-6-methoxybensothiazole (1.17 g) andmalononitrile (0.82 g), and hydrazine hydrate (0.2 mL) in ethanol.Solids had not formed after heating the reaction at 40° C. for 2 hrs.The solution was allowed to cool to ambient temperature andconcentrated. The product was obtained after column chromatographypurification (80 mg, 35%).

43. 4-(benzothiazol-2-ylhydrazono)-4H-pyrazole-3,5-diamine was preparedusing 2-[(6-benzothiazol-2-yl)hydrazono]malononitrile (80 mg), which wasderived from 2-aminobensothiazole (925 mg) and malononitrile (0.65 g),and hydrazine hydrate (0.1 mL) in ethanol. Solids had not formed afterheating the reaction at 60° C. for 3 hrs. The solution was allowed tocool to ambient temperature and concentrated. The product was obtainedafter thin layer chromatography purification (47 mg, 50%).

44. 4-[(1H-pyrazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 3-aminopyrazole (0.5 g), malononitrile (1.8 g), and hydrazinehydrate (0.3 g). The product was obtained after column chromatographypurification (157 mg, 14%).

45. 4-[(4H-[1,2,4]-triazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared by using 3-amino-1,2,4-triazole (0.88 g), malononitrile (1.0g), and hydrazine hydrate (0.5 ml) to yield 34 mg of the compound (6%).

46. 4-[(3,5-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared by using 3,5-difluoroaniline (0.31 g), malononitrile (0.4 g)and hydrazine hydtrate (0.2 g) to yield 0.201 g of the compound (35%).

47. 4-[(2,3,4-trifluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared by using 2,3,4-trifluoroaniline (0.36 g), malononitrile (0.4 g)and hydrazine hydrate (0.2 g) to yield 0.337 g of the compound (54%).

48. 1-methyl-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using2-phenylhydrazonomalononitrile (425 mg) and methylhydrazine sulfate (720mg). The compound was purified by column chromatography and afforded ayellow solid.

49.7-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-4-trifluoromethylchroman-2-onewas prepared from 7-amino-4-trifluoromethylchromen-2-one (0.25 g),malononitrile (0.15 g) and hydrazine hydrate (0.3 mL). The compound(0.101 g) was isolated after purification by column chromatography.

50. 4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide wasprepared from 4-aminobenzenesulfonamide (0.344 g, 2 mmol), malononitrile(0.172 g, 2.6 mmol) and hydrazine hydrate (0.03 g, 0.6 mmol). Filtrationand washing with cold ethanol afforded the compound as a yellow powder(0.139 g); MS (m/z, ES+): 282 (M+1, 100%); ¹H NMR (ppm, 200 MHz,DMSO-d₆) δ 10.97 (br. s, 1H), 7.96-7.50 (m, 4H), 7.30 (br. s, 2H), 6.44(br. s, 2H), 6.02 (br. s, 2H).

51.4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2,6-dimethylpyrimidin-4-yl)benzenesulfonamidewas prepared from4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzenesulfonamide (0.557 g, 2mmol), malononitrile (0.172 g, 2.6 mmol) and hydrazine hydrate (0.03 g,0.6 mmol). Filtration and washing with cold ethanol afforded thecompound as an orange-red powder (0.195 g); MS (m/z, ES+): 388 (M+1,100%); ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 11.75 (br. s, 1H), 7.81 (d, 2H),7.76 (d, 2H), 6.80 (s, 1H), 6.48 (br. s, 2H), 6.0 (br. s, 2H), 2.38 (s,3H), 2.24 (s, 3H).

52.4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(pyrimidin-2-yl)benzenesulfonamidewas prepared from 4-amino-N-pyrimidin-2-ylbenzenesulfonamide (0.500 g, 2mmol), malononitrile (0.172 g, 2.6 mmol) and hydrazine hydrate (0.03 g,0.6 mmol). Filtration and washing with cold ethanol afforded thecompound as a yellow powder (0.175 g). MS (m/z, ES+): 360 (M+1, 100%).

53. 4-[(4-methoxy-3-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared using methoxy-3-nitroaniline (0.35 g, mmol), malononitrile (0.4g), and hydrazine hydrate (0.3 mL). The compound was filtered off andrecrystallized from EtOH yielding 0.21 g (36%). MS (m/z, ES+): 278.1(M+1, 100%).

Example 3 Preparation of4-(pyridin-4-ylhydrazono)-4H-pyrazole-3,5-diamine

4-(pyridin-4-ylhydrazono)-4H-pyrazole-3,5-diamine was prepared bydissolving 4-aminopyridine (0.36 g) in a mixture of 2 ml of H₃PO₄ (85%)and 1 ml of HNO₃ (68%). The solution was cooled at −5° C. and then NaNO₂(0.28 g) solution was added. After being stirred at 0° C. for 1 hr, themixture was added dropwise into a solution of malononitrile (0.5 g),acetic acid (2.4 g), KOAc (6.3 g) and Na₂CO₃ (5.6 g). The resultingmixture was kept stirring at 0° C. for 1 hr, and 100 mL of water wasadded. The solid obtained after being filtered and dried wasre-dissolved in 5 mL of EtOH and hydrazine hydrate (0.5 g) was added at40° C. After one hour of reaction, the solid precipitated upon coolingto 0° C. was collected by filtration and the title compound was obtainedafter re-crystallization from EtOH (278, mg, 36%).

Example 4 Preparation of4-(2,3,4,5,6-pentafluorophenylhydrazono)-4H-pyrazole-3,5-diamine

Pentafluoroaniline (1.0 g) dissolved in 12 mL of CH₃COOH was added to asolution of NaNO₂ (0.41 g) in concentrated H₂SO₄ at 5° C. The reactionmixture was kept stirring at 5° C. for 1 hr and then slowly added to asolution of malononitrile (1.0 g) mixed with 37 g of NaOAc in 50 mL ofH₂O at 5-10° C. The reaction mixture was extracted with ethyl acetate(EtOAc) (3×150 mL) an hour later. The combined organic phase was washedwith brine, dried with anhydrous MgSO₄ and then evaporated. The residuewas dissolved in 5 ml of anhydrous EtOH and 0.2 g of N₂H₄ was added toit at 40° C. After being stirred at 70° C. for 2 hrs, the solvents wereremoved and the residue was purified by column yielding 87 mg of thetitle compound (5.4%).

Example 5 Preparation of4-(benzo[1,2,5]thiadiazol-4-ylhydrazono)-4H-pyrazole-3,5-diamine

To a solution of 4-amino-2,1,3-benzothiadiazole (0.38 g, 2.5 mmol) in amixture of DMF (4 mL) and water (3.6 mL) at 0° C. was added 0.58 mL ofconcentrated HCl. This mixture was then added to a solution of sodiumacetate trihydrate (1.4 g, 10 mmol) and malononitrile (0.3 g, 4.5 mmol)in water (7 mL) at 5° C. A precipitate formed immediately. Afterstirring for 2 hours, the solid was isolated by filtration and dried invacuo. The solid was then dissolved in ethanol (20 mL) at 45° C. To thissolution was added hydrazine hydrate (0.3 g, 6.0 mmol) and heating wascontinued for 1 hour. A solid precipitated from the solution and wasisolated by filtration to afford 0.41 g of crude material. The crudematerial (0.1 g) was purified by preparative TLC eluting withCHCl₃:MeOH=4:1 to yield 0.029 g (18%) of the title compound as a yellowsolid.

Example 6 Preparation of4-[(4-fluoro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine

A. Sodium acetate trihydrate (28 g, 203 mmol) was dissolved in 140 mL ofwater. Malononitrile (12 g, 182 mmol) was added and the solution wasstirred until all the solids had dissolved. This solution was allowed tocool in an ice bath to approximately 0° C. and put aside. A solution of4-fluoro-3-trifluoromethylaniline (17.9 g, 100 mmol) in 24 mL of waterand 30 mL of DMF was cooled to 0° C. Concentrated HCl (23.2 mL) wasadded. A cooled solution of sodium nitrite (9.2 g, 133 mmol) in 20 mL ofwater was then added at a rate such that the temperature did not exceed5° C. The phenyldiazo salt solution was added slowly to themalononitrile solution at a rate such that the temperature did notexceed 7° C. Yellow precipitate formed upon the addition. The solutionwas stirred for one hour. The resulting solid was isolated by filtrationand dried under high vaccum.

B. A solution of the material prepared above in 200 mL of anhydrousethanol was warmed to 30° C. until all of the solids had dissolved.Hydrazine hydrate (5 mL, 100 mmol) was added drop wise to the stirringsolution. Heating was continued for seven hours. The solvent wasevaporated from the reaction solution. The resulting solids weredissolved in ethyl acetate (<20 mL/g) and precipitated by the additionof hexanes (up to 60 mL/g) to provide the title compound as a yellowsolid (16.4 g, 57%); IR (cm⁻¹, KBr pellet): 531, 585, 642, 670, 742,775, 832, 901, 923, 942, 1046, 1127, 1157, 1241, 1261, 1290, 1321, 1403,1433, 1495, 1515, 1564, 1599, 1627, 3309; ¹H NMR (ppm, 200 MHz, DMSO-d₆)δ 10.8 (S, 1H), 8.05 (dd, 1H), 8.0 (m, 1H), 7.5 (t, 1H), 6.2 (brs, 4H);MS (m/z, ES+): 289.1 (M+1, 100%); Anal. Calcd for C₁₀H₈F₄N₆: C, 41.67;H, 2.80; N, 29.16. Found: C, 41.13; H, 3.04; N, 28.85.

Example 7 Preparation of4-[(3-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine

4-[(3-Nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using2-[(3-nitrophenyl)hydrazono]malononitrile (0.107 g, 0.5 mmol) which wasderived from 3-nitroaniline (0.133 g, 1.0 mmol) and malononitrile (1.5mmol) in a manner similar to that described in Example 2, and hydrazinehydrate. The resulting solid (0.088 g) was isolated by filtration, aportion (0.060 g) of which was purified by flash chromatography to yield0.024 g (28%) of the title compound as an orange solid; MS (m/z, ES+):248.0 (M+1, 100%).

Example 8 Preparation of{2-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol

{2-[N′-(3,5-Diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol wasprepared using 2-[(2-hydroxymethylphenyl)hydrazono]malononitrile (0.100g, 0.5 mmol) which was derived from 3-aminobenzyl alcohol (0.123 g, 1.0mmol) and malononitrile (1.5 mmol) in a manner similar to that describedin Example 2, and hydrazine hydrate. The title compound was obtained asa brown solid (32 mg, yield 28%); ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 4.51(d, 2H), 5.20 (t, 1H), 6.0 (br s, 4H), 7.15 (d, 1H), 7.30 (t, 1H),7.45-7.60 (m, 2H), 10.60 (br s, 1H).

Example 9 Preparation of4-[(1H-indazol-5-yl)hydrazono]4H-pyrazole-3,5-diamine 37091

4-[(1H-Indazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine was preparedusing 2-[(1H-indazol-5-yl)hydrazono]malononitrile (0.105 g, 0.5 mmol)which was derived from 5-aminoindazole (0.133 g, 1.0 mmol) andmalononitrile (1.5 mmol) in a manner similar to that described inExample 2, and hydrazine hydrate. The resulting solid was isolated byfiltration, washed with ethanol, and dried to yield 0.076 g (63%) of thetitle compound as a brown solid; ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 6.0(br s, 4H), 7.50 (d, 1H), 7.94 (d, 1H), 8.0 (s, 1H), 8.08 (s, 1H), 10.68(br s, 1H), 13.08 (s, 1H).

Example 10 Preparation of4-(quinolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine

4-(Quinolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine was prepared using2-(quinolin-6-ylhydrazono)malononitrile (0.11 g, 0.5 mmol) which wasderived from 6-aminoquinoline (0.144 g, 1.0 mmol) and malononitrile (1.5mmol) in a manner similar to that described in Example 2, and hydrazinehydrate. The resulting solid was isolated by filtration and purified byflash chromatography to yield 0.025 g (20%) of the title compound as anorange solid; ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 5.95 (br s, 2H), 6.45 (brs, 2H), 7.40-7.55 (m, 1H), 7.98 (d, 1H), 8.10 (s, 1H), 8.20-8.40 (m,2H), 8.79 (d, 1H), 10.35 (brs, 1H).

Example 11 Preparation of{4-[N-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzyl}phosphonic aciddiethyl ester

{4-[N′-(3,5-Diaminopyrazol-4-ylidene)hydrazino]benzyl}phosphonic aciddiethyl ester was prepared using[4-(N′-dicyanomethylenehydrazino)benzyl]phosphonic acid diethyl ester(0.16 g, 0.5 mmol) which was derived from diethyl4-aminobenzylphosphonate (0.243 g, 1.0 mmol) and malononitrile (1.5mmol) in a manner similar to that described in Example 2, and hydrazinehydrate. The title compound was purified by flash chromatography andisolated as a golden solid (0.116 g, 66%); ¹H NMR (ppm, 200 MHz,DMSO-d₆) δ 1.20 (t, 6H), 3.23 (d, 2H), 3.95 (q, 4H), 6.0 (brs, 4H), 7.28(d, 2H), 7.60 (d, 2H), 10.70.

Example 12 Preparation of4-(benzo[2,1,3]thiadiazol-5-ylhydrazono)-4H-pyrazole-3,5-diamine

A. To a suspension of MoCl₅ (8 g) in 50 ml of THF was added 10 ml of H₂Oand followed by the addition of Zn dust (3 g) 5 minutes later.5-Nitrobenzo-2,1,3-thiadiazole (1.0 g) was then added to this mixtureand the resulting reaction mixture was kept under reflux for 20 minutes.Benzo[1,2,5]thiadiazol-5-ylamine (0.4 g) was isolated by filtration andpurified by column chromatography to be used in the next step.

B. The title compound was prepared by usingbenzo[1,2,5]thiadiazol-5-ylamine (0.19 g), malononitrile (0.15 g) andhydrazine hydrate (0.3 mL) in a manner similar to that described inExample 2. The title compound was purified by column chromatography toyield 0.047 g (14%).

Example 13 Preparation of4-[(3-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine

A. To a suspension of 3-methylthioaniline (0.278 g, 2 mmol) in 3 mL ofwater cooled in an ice bath was added 0.5 mL of conc. HCl (6 mmol). Anaqueous solution of NaNO₂ (0.179 g, 2.6 mmol) was slowly added to themixture. A red color solution obtained was kept stirring at −5° C. for 5minutes, and then added to the mixture of malononitrile (0.172 mg, 2.6mmol) and NaOAc.3H₂O (0.816 g, 6 mmol) in 3 mL of water. The mixture wasstirred at ambient temperature for an hour, and the intermediate wascollected by filtration and dried in vacuum to yield a brown yellowpowder (0.433 g), which was used for the next step.

B. The intermediate obtained above (0.108 g, 0.5 mmol) was suspended in2 mL of ethanol and 1 mL of ethanol solution of hydrazine (30 mg, 0.6mmol) was added to the suspension. The mixture was heated to reflux foran hour. Upon cooling to ambient temperature, a yellow precipitation wasobtained. Filtration and washing with ethanol afforded 0.128 g of thetitle compound. MS (m/z, ES+): 249 (M+1, 100%).

Example 14 Preparation of4-[(3-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine

To a 1.5 mL methanol solution of the intermediate obtained in Example 65(0.065 g, 0.3 mmol) in an ice bath was added 1 mL of aqueous solution ofNaIO₄ (0.086 g, 0.4 mmol). The reaction process was monitored by TLC.The reaction mixture was filtrated after the disappearance of thestarting material on TLC. The filtrate was evaporated to dryness andthen re-dissolved in ethanol. Hydrazine (30 mg, 0.6 mmol) was added tothe ethanol solution. The mixture was heat at 60° C. for 2 hours. Thetitle compound was obtained as an orange-yellow powder after purified bypreparative-TLC (0.036 g); MS (m/z, ES+): 265 (M+1, 100%). ¹H NMR (ppm,200 MHz, DMSO-d₆) δ 10.84 (br. s, 1H), 7.95 (s, 1H), 7.80 (m, 1H), 7.60(m, 1H), 7.50 (m, 1H), 6.42 (br. s, 2H), 5.99 (br. s, 2H), 2.80 (s, 3H).

Example 15 Preparation of4-(quinazolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine

A. Quinazoline (2 g) was nitrated with 25 mL of mixture of nitric acid90%, 10 mL) and sulfuric acid (+20% SO₃, 15 mL) at 0° C. for 20 minutes,and then at ambient temperature for 1 hour. The mixture was then pouredon ice, neutralized with KOH and the pH was adjusted to 8 with K₂CO₃ (pH8). Filtration and recrystallization from EtOH yielded the crystallineproduct 6-nitroquinazoline (1.7 g).

B. SnCl₂ (8.5 g) dissolved in 8.5 mL of conc. HCl was added to thesolution of 6-nitroquinazoline in 42.5 mL of 6 N HCl at 0° C. Thereaction mixture was neutralized with KOH 10 minutes later and thenextracted with diethyl ether (Et₂O) and EtOAc. The product6-aminoquinazoline was obtained (0.67 g) after the removal of thesolvent.

C. In a manner similar to that described in Example2,4-(quinazolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine was preparedusing 6-aminoquinazoline (0.27 g), malononitrile (0.2 g) and hydrazinehydrate (0.4 g) to yield 0.067 g (14%) of the title compound: MS (m/z,ES+): 255.3 (M+1, 100%).

Example 16 Preparation of4-[(1-methyl-1H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine

A. 1-Methyl-5-nitrobenzotriazole (0.7 g) was reduced by SnCl₂ (4.0 g) at0° C. in 5 mL of conc. HCl. The pH of the reaction mixture was adjustedto basic and the mixture was extracted with EtOAc. The product5-amino-1-methylbenzotriazole (0.4 g) obtained after removal of thesolvent was used for the next reaction without further purification.

B. The title compound was prepared following the similar procedure asdescribed in Example 2. 5-Amino-1-methylbenzotriazole (0.25 g),malononitrile (0.17 g) and hydrazine hydrate (0.3 g) yielded 0.151 g(35%) of the title compound after recrystallization from EtOH; MS (m/z,ES+): 258.1 (M+1, 100%).

Example 17 Preparation of4-[(3-methyl-3H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine

A. 3-Methyl-5-nitrobenzotriazole (0.8 g) was reduced by SnCl₂ (4.5 g) at0° C. in 5 mL of conc. HCl. The pH of the reaction mixture was adjustedto basic and the mixture was extracted with EtOAc. The product,5-amino-3-methylbenzotriazole (0.6 g), obtained after removal of thesolvent, was used for the next reaction without further purification.

B. 4-[(3-methyl-3H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared following the similar procedure as described in Example 2.5-Amino-3-methylbenzotriazole (0.25 g), malononitrile (0.2 g) andhydrazine hydrate (0.3 g) yielded 0.188 g (44%) of the title compoundafter recrystallization from EtOH; MS (m/z, ES+): 258.1 (M+1, 100%).

Example 18 Preparation of 1-benzyl-4-phenylazo-1H-pyrazole-3,5-diamine

1-Benzyl-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using2-(phenyl-hydrazono)malononitrile (0.085 g, 0.5 mmol), which was derivedfrom aniline (10 mL, 107 mmol) and malononitrile (161 mmol), asdescribed in Example 2. The following change was made to the procedure:Benzylhydrazide dihydrochloride (0.097 g, 0.5 mmol) was used in theplace of hydrazine hydrate. Additionally, 0.25 mL of 2 M sodiumhydroxide solution was added to the reaction tube. Solids had not formedafter heating the reaction at 75° C. for 3 hours, however, analysis ofthe reaction solution by TLC indicated that no starting materialremained. The solvent was evaporated and the solids were redissolved in1 M HCl solution, which was then washed with diethyl ether. The aqueouslayer was neutralized with saturated NaHCO₃ solution and extracted threetimes with ethyl acetate. The combined organic layers were dried overMgSO₄, filtered and evaporated. This material was then purified by flashchromatography eluting with CH₂Cl₂:MeOH (20:1) to yield 0.013 g (9%) ofthe title compound as an orange solid; ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ4.95 (s, 2H), 5.9 (br s, 2H), 6.75 (br s, 2H), 7.20-7.45 (m, 8H), 7.68(d, 2H).

Example 19 Preparation of1-{2-[3,5-diamino-4-(pyridin-3-ylazo)pyrazol-1-yl]-2-oxoethyl}pyrrolidine-2-carboxylicacid methyl ester

A. A mixture of L-proline methyl ester (2.7 g, 16 mmol), K₂CO₃ (4.9 g,35.5 mmol) and benzyl 2-bromoacetate (3.6 g, 16 mmol) in 18 mL oftoluene was heated to 86° C. for 5 hours. The milky suspension was thencooled to ambient temperature and treated with aqueous NaHCO₃ and ethylacetate. The collected organic phase was extracted with 10% HCl. Theacid phase was neutralized to pH 10 with K₂CO₃ and extracted with ethylacetate. The organic layer was washed with saline, dried and evaporatedto dryness. A pale brown liquid was obtained in 2.5 g, yield 59%. MS(m/z, ES+): 278 (M+1, 100%); ¹H NMR (ppm, 300 MHz, DMSO-d₆): 7.36 (m,5H), 5.10 (s, 2H), 3.60 (d, J=17 Hz, 1H), 3.57 (s, OCH₃), 3.52 (dd, 1H),3.49 (d, J=17 Hz, 1H), 3.00 (m, 1H), 2.67 (dd, 1H), 2.02 (m, 1H),1.65-1.90 (m, 3H).

B. Ethanol solution (2 mL) ofN-benzyloxycarbonylmethylpyrrolindine-2-carboxylic acid methyl ester(0.534 g, 2 mmol) prepared above and Pd/C (10%, 8.9 mg) was stirredunder H₂ atmosphere for 4 hours. Acetic acid (3 drops) was then added.After the reaction, the solution was filtrated through a celite plug.After solvent evaporation, the residue oil was mixed withN-hydroxysuccinimide (0.276 g, 2.5 mmol) and suspended in 5 mL ofethylene glycol dimethyl ether. To this mixture was added DCC (0.515 g,2.5 mmol) solution in 3 mL of ethylene glycol ether. After stirred atambient temperture overnight, the reaction mixture was filtrated toremove DCU powder. The filtrate is directly used in next reaction.

C. The NHS ester solution made above (5 mL) was slowly added to thesolution of 5-amino-4-(nicotinylhydrazono)-3-amino-4H-pyrazole (0.226 g,1 mmol) and triethylamine (0.101 g, 1 mmol) in 8 mL of DMF at 78° C.Saline and ethyl acetate were added to the reaction mixture 1 hourlater. The collected organic layer was concentrated and purified bycolumn chromatography eluted with CH₂Cl₂:MeOH (15:1). A sticky solid wasobtained as the title compound (0.180 g, 50%); MS (m/z, ES+): 373 (M+1,32%), 204 (100%); ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 8.98 (d, 1H), 8.46(dd, 1H), 8.26 (br. s, NH₂), 8.14 (ddd, 1H), 7.45 (dd, 1H), 6.33 (br. s,NH₂), 4.11 (d, J=18.6 Hz, 1H), 3.99 (d, J=18.6 Hz, 1H), 3.63 (dd, 1H),3.60 (s, OCH), 3.09 (m, 1H), 2.80 (dd, 1H), 2.09 (m, 1H), 1.69-1.93 (m,3H).

Example 20 Preparation of3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide

3-Aminobenzosulfonamide (0.33 g, 1.92 mmol) was dissolved in 3.6 mL ofH₂O and 0.56 mL of conc. HCl was added. The mixture was treated withNaNO₂ (0.22 g, 3.19 mmol) in 0.5 mL of H₂O at 0° C. This diazonium saltsolution was then added into the mixture of malononitrile solution (0.3g) and NaOAc trihydrate (1.4 g) in 8 mL of H₂O at 10° C. The solidproduct, collected by filtration and used directly for next reaction,was re-dissolved in 20 mL of EtOH. Hydrazine hydrate (0.3 mL) was addedto the solution and the mixture was kept at 55° C. for about an hour.The title compound was obtained in a yield of 20% (0.110 g); MS (m/z,ES+): 282.1 (M+1, 100%).

Example 21 Preparation of4-(isoquinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine

5-Aminoisoquinoline (5 g, 34.7 mmol) was dissolved in 150 mL of anaqueous solution containing 58.8 g of sulfuric acid. This mixture wascooled to 0° C. and a solution of sodium nitrite (4 g, 58 mmol)dissolved in 10 mL of water was added drop-wise. This solution was thenslowly added to a mixture of malononitrile (4 g, 61 mmol) and sodiumacetate trihydrate (165 g, 1.2 mol) dissolved in 300 mL of water at 0°C. A red precipitate formed which was isolated by filtration. The aboveformed product was suspended in 150 mL of ethanol and hydrazine hydrate(4.0 mL, 122 mmol) was added. The reaction was heated to reflux for 4hours. The solvent was then evaporated and the crude material waspurified by silica gel chromatography eluting with CHCl₃:MeOH=5:1 to 3:1to yield 5.14 g (29%) of the title compound as a yellow solid; IR (cm⁻¹,KBr pellet): 3428 (s), 3174 (s), 1639 (s), 1596 (s), 1556 (s), 1510 (s),1477 (s), 1368 (s), 1329 (m), 1307 (s), 1269 (s), 1232 (m), 1206 (m),1138 (s), 1090 (w), 1028 (m), 904 (w), 820 (m), 805 (s), 745 (s), 653(m), 589 (m); ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 10.95 (s, 1H), 9.25 (s,1H), 8.5 (d, 1H), 8.35 (d, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.85 (t,1H), 6.3 (br s, 4H); MS (m/z, ES+): 254.2 (M+1, 25%); Anal. Calcd forC₁₂H₁₁N₇: C, 56.91; H, 4.38; N, 38.71. Found: C, 56.35; H, 4.35; N,38.86.

Example 22 Preparation of Compounds of the Invention where R5 is aryl

A. An aqueous solution (1 mL) of NaNO₂ (83 mg; 1.2 mmol) was addeddropwise to a stirred solution of an appropriately optionallysubstituted aniline (1.0 mmol) in 10% HCl (4 mL) under ice-cooling.After 15 minutes this solution was added dropwise to a cold solution ofmalononitrile (79 mg; 1.2 mmol) in aqueous sodium acetate (1.4 g in 7 mLof H₂O). A precipitate (yellow to brown) was filtered off, washed withwater and dried in vacuum.

B. To a stirred solution of the appropriately optionally substituted(arylhydrazono)malononitrile (0.75 mmol) obtained above in THF (35 mL)was added dropwise a solution of hydrazine hydrate (1 mmol) in THF (10mL) at 55° C., and the mixture was stirred for 30 minutes. The solventwas evaporated and the residue was re-crystallized from ethanol orethanol/chloroform mixture.

C. In the manner described above, the following compounds of theinvention were prepared:

1. 192 mg of4-[(4-nitro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 515 mg (2.5 mmol) of4-nitro-3-(trifluoromethyl)aniline. MS (m/z, ES+): 316 (M+1). Yield=61%.

2. 255 mg of4-[(4-chloro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 195.5 mg (1.0 mmol) of5-amino-2-chlorobenzotrifluoride. MS (m/z, ES+): 305 (M+1). Yield 83%.

3. 249 mg of4-[(2,2-difluorobenzo[1,3]dioxol-5-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 195.0 mg (1.13 mmol) of2,2-difluorobenzo[1,3]dioxol-5-ylamine. MS (m/z, ES+): 283 (M+1). Yield78%.

4. 299 mg of4-[(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 245.0 mg (1.1 mmol) of2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-ylamine. MS (m/z,ES+): 333 (M+1). Yield 82%.

5. 254 mg of4-[(4-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 225.0 mg (1.0 mmol) of4-trifluoromethanesulfonylphenylamine. MS (m/z, ES+): 335 (M+1). Yield76%.

6. 78 mg of 4-[(4-phenylaminophenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 184.0 mg (1.0 mmol) ofN-phenylbenzene-1,4-diamine. MS (m/z, ES+): 294 (M+1). Yield 27%.

7. 303 mg ofN-butyl-3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamidewas prepared in two steps starting with 228.0 mg (1.0 mmol) of3-amino-N-butylbenzenesulfonamide. MS (m/z, ES+): 338 (M+1). Yield 90%.

8. 145 mg of4-[(3-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared in two steps starting with 171.0 mg (1.0 mmol) of3-methanesulfonylphenylamine. MS (m/z, ES+): 281 (M+1). Yield 52%.

9. 234 mg 4-[(4-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 171.0 mg (1.0 mmol) of4-methanesulfonylphenylamine. MS (m/z, ES+): 281 (M+1). Yield 83%.

10. 202 mg of4-{[4-(morpholine-4-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 181.0 mg (0.75 mmol) of4-(morpholinosulfonyl)aniline. MS (m/z, ES+): 352 (M+1). Yield 77%.

11. 205 mg4-{[4-(pyrrolidine-1-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 170.0 mg (0.75 mmol) of4-(tetrahydro-1H-pyrrol-1-ylsulfonyl)aniline. MS (m/z, ES+): 336 (M+1).Yield 82%.

12. 238 mg of4-[(1,1-dioxo-1H-benzo[b]thiophen-6-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 179.0 mg (0.99 mmol) of1,1-dioxo-1H-1λ⁶-benzo[b]thiophen-6-ylamine. MS (m/z, ES+): 291 (M+1).Yield 83%.

13. 175 mg of4-[(4-morpholin-4-ylphenyl)hydrazono]4H-pyrazole-3,5-diamine wasprepared in two steps starting with 178.0 mg (1.0 mmol) of4-(morpholin-4-yl)phenylamine. MS (m/z, ES+): 288 (M+1). Yield 61%.

14. 142 mg of4-[(3-chloro-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 160.0 mg (0.75 mmol) of3-chloro-4-(morpholin-4-yl)phenylamine. MS (m/z, ES+): 322. Yield 59%.

15. 71 mg of4-[(4-(piperidin-1-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared in two steps starting with 176 mg (1.0 mmol) of4-(piperidin-1-yl)phenylamine. Yield=25%. MS (m/z, ES+): 286 (M+1).

16. 42 mg of 4-(phthalazin-5-ylhydrazono)-4H-pyrazole-3,5-diamine wasprepared in two steps starting with 75 mg (0.5 mmol) ofphthalazin-5-ylamine. Yield 33%. MS (m/z, ES+): 253.1 (M+1).

17. 242 mg of 4-[(4-benzylphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared in two steps starting with 183 mg (1.0 mmol) of4-benzylphenylamine. Yield 82.8%. MS (m/z, ES+): 293 (M+1).

18. 345 mg of4-[(6-(piperidin-1-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in five steps starting with 317 mg (2.0 mmol) of2-chloro-5-nitropyridine. Yield 60.0%. MS (m/z, ES+): 287 (M+1).

19. 28 mg of4-{[6-(4-methylpiperazin-1-yl)pyridin-3-yl]hydrazono}-4H-pyrazole-3,5-diamine(isolated by preparative TLC) was prepared in five steps starting with158.5 mg (1.0 mmol) of 2-chloro-5-nitropyridine. Yield 9.3%. MS (m/z,ES+): 302.1 (M+1, 30%).

20. 208 mg of4-[(6-(morpholin-4-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in five steps starting with 158.5 mg (1.0 mmol) of2-chloro-5-nitropyridine. Yield 72%. MS (m/z, ES+): 289.3 (M+1).

21. 273 mg of4-[(3-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 225 mg (1.0 mmol) of3-trifluoromethanesulfonylphenylamine. Yield 82%. MS (m/z, ES+): 335(M+1).

22. 12.5 mg of4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-diethylaminomethylphenol(isolated by preparative TLC) was prepared in two steps starting with145.5 mg (0.75 mmol) of 4-amino-2-diethylaminomethylphenol. Yield 5.5%.MS (m/z, ES+): 304.3 (M+1).

23. 277 mg of2-{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanolwas prepared in two steps starting with 225 mg (1.0 mmol) of2-(3-aminobenzenesulfonyl)ethanol. Yield 89.3%. MS (m/z, ES+): 311.2(M+1).

24. 25 mg of2-[{5-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]pyridin-2-yl}(2-hydroxyethyl)amino]ethanol(isolated by preparative TLC) was prepared in five steps starting with158.5 mg (1.0 mmol) of 2-chloro-5-nitropyridine. Yield 8.1%. MS (m/z,ES+): 307.1 (M+1, 80%).

25. 191 mg of 4-(4-(phenyl)phenylhydrazono)-4H-pyrazole-3,5-diamine wasprepared in two steps starting with 169 mg (1.0 mmol) ofbiphenyl-4-ylamine. Yield 68.9%. MS (m/z, ES+): 279.3 (M+1).

26. 133 mg of4-[(2,3-difluoro-4-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 98.5 mg (0.5 mmol) of4-amino-2,3-difluorobenzotrifluoride. Yield 87%. MS (m/z, ES+): 307.8(M+1, 100%).

27. 237 mg of4-[(2,6-dimethoxypyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared in two steps starting with 154 mg (1.0 mmol) of2,6-dimethoxypyridin-3-ylamine. Yield 90%. MS (m/z, ES+): 264 (M+1).

28. 161 mg of4-{[4-(4-methylaminobenzyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine wasprepared in two steps starting with 212 mg (2.0 mmol) of4-(4-methylaminobenzyl)phenylamine. Yield 50%. MS (m/z, ES+): 321 (M+1).

29. 77 mg of4-[(3-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 192 mg (1.0 mmol) of3-(morpholin-4-yl)methylphenylamine. Yield 26%. MS (m/z, ES+): 302(M+1).

30. 248 mg of4-[(3-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 190 mg (1.0 mmol) of3-(piperidin-1-yl)methylphenylamine. Yield 83%. MS (m/z, ES+): 300.9(M+1).

31. 245 mg of4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamidewas prepared in three steps starting with 216 mg (1.0 mmol) ofN-methyl-4-nitrobenzenesulfonamide. Yield 83%. MS (m/z, ES+): 296.1(M+1).

32. 154 mg of3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamidewas prepared in three steps starting with 216 mg (1.0 mmol) ofN-methyl-3-nitrobenzenesulfonamide. Yield 52%. MS (m/z, ES+): 296.3(M+1).

33. 105 mg of4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamidewas prepared in two steps starting with 120 mg (0.6 mmol) of4-amino-N-ethylbenzenesulfonamide. Yield 56%. MS (m/z, ES+): 310.6(M+1).

34. 330 mg of3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamidewas prepared in two steps starting with 240 mg (1.2 mmol) of3-amino-N-ethylbenzenesulfonamide. Yield 89%. MS (m/z, ES+): 310.7(M+1).

35. 164 mg of4-[(4-methyl-3-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 310 mg (1.61 mmol) of4-methyl-3-(morpholin-4-yl)phenylamine. Yield 47%. MS (m/z, ES+): 302(M+1, 100%). ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 2.25 (s, 3H), 2.95-3.05(t, 4H), 3.65-3.75 (t, 4H), 5.3-6.5 (m, 4H), 6.8 (d, 1H), 6.85 (s, 1H),7.55 (d, 1H), 10.8 (br s, 1H).

36. 286 mg of4-[(3-fluoro-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 185 mg (1.033 mmol) of3-amino-5-fluorobenzotrifluoride. Yield 96%. MS (m/z, ES+): 289.1 (M+1).

37. 174 mg of4-[(4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 281 mg (1.46 mmol) of4-(morpholin-4-yl)methylphenylamine. Yield 39%. MS (m/z, ES+): 302(M+1).

38. 159 mg of4-{[4-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 205 mg (1.00 mmol) of4-(4-methylpiperazin-1-yl)methylphenylamine. Yield 50.6%. MS (m/z, ES+):315 (M+1, 20%). ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 2.1 (s, 3H), 2.2-2.5(br m, 4H), 3.15-3.25 (br m, 4H), 3.45 (s, 2H), 5.5-6.5 (br m, 4H), 7.25(d, 2H), 7.55 (d, 2H), 10.75 (s, 1H).

39. 264 mg of4-[(4-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 190 mg (1.00 mmol) of4-(piperidin-1-yl)methylphenylamine. Yield 88.2%. MS (m/z, ES+): 300(M+1, 20%). ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 1.2-1.6 (br m, 6H),2.2-2.35 (br m, 4H), 3.4 (s, 2H), 5.5-6.5 (br m, 4H), 7.25 (d, 2H), 7.55(d, 2H), 10.75 (s, 1H).

40. 145 mg of4-{[4-(2-(morpholin-4-yl)ethyl)phenyl]hydrazono}-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 206 mg (1.00 mmol) of4-(2-(morpholin-4-yl)ethyl)phenylamine. Yield 46.0%. MS (m/z, ES+): 316(M+1, 100%). ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 2.2-2.6 (br, m, 6H),2.6-2.8 (br, m, 2H), 3.4-3.6 (m, 4H), 5.5-6.5 (br, m, 4H), 7.20 (d, 2H),7.50 (d, 2H), 10.7 (s, 1H).

41. 237 mg of4-[(3-(morpholin-4-ylmethyl)-5-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 302 mg (1.27 mmol) of3-(morpholin-4-yl)methyl-5-nitrophenylamine. Yield 53.7%. MS (m/z, ES+):347 (M+1). ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 2.3-2.5 (br, m, 4H), 3.5-3.7(br, m, 4H), 3.55 (s, 2H), 5.5-6.5 (br, m, 4H), 7.95 (s, 1H), 8.0 (s,1H), 8.35 (s, 1H), 10.75 (s, 1H).

42. 181 mg of4-{[3-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 335 mg (1.63 mmol) of3-((4-methylpiperazin-1-yl)methyl)phenylamine. Yield 40.8%. MS (m/z,ES+): 315 (M+1, 60%).

43. 97 mg of4-[(3-(pyrrolidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 242 mg (1.37 mmol) of3-(pyrrolidin-1-yl)methylmethylphenylamine. The final product wasisolated by column purification followed by precipitation from ethylacetate by addition of hexane. Yield 21.0%.

44. 145 mg of4-({3-[2-(2-methoxyethoxy)ethoxymethyl]phenyl}hydrazono)-4H-pyrazole-3,5-diaminewas prepared in two steps starting with 206 mg (1.00 mmol) of4-(2-morpholin-4-ylethyl)phenylamine. The final product was isolated bycolumn purification followed by precipitation from ethyl acetate byaddition of hexane. Yield 46.0%. MS (m/z, ES+): 335 (M+1, 100%).

Example 23 Preparation of4-[(2-methyl-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine

2-Methyl-4-morpholin-4-ylphenylamine (170 mg, 0.885 mmol) was dissolvedin 2N HCl (8 mL). A solution of NaNO₂ (69 mg) in water (2.5 mL) wasadded at 0° C. and the green solution was stirred for 15 minutes andthen added dropwise to the cooled (0° C.) solution of malononitrile (69mg; 1.0 mmol) in water:NaOAc (5 mL) with stirring. The dark brown solidwas filtered off, dried on filter in vacuum, and then dissolved inether:THF mixture 3:1 (25 mL). Hydrazine hydrate (80 μL) was added inone portion at ambient temperature. The solution was then heated at 40°C. for 15 minutes, and the solvents were evaporated. The dark yellowsolid was precipitated from ethyl acetate via addition of hexane,filtered and dried to provide 100 mg of the title compound (yield 33%);MS (m/z, ES+): 302.2 (M+1, 100%).

Example 24 Preparation of{2-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol

A. To a solution of 2-hydroxymethylaniline (2.46 g, 0.02 mol) in 2 N HCl(80 mL) was added a solution of sodium nitrite (1.65 g, 24 mmol) inwater (20 mL) at 5° C. The resulting reaction mixture was stirred for 10minutes before it was added dropwise to a solution of malononitrile(1.58 g, 24 mmol) and sodium acetate (17 g) in water (150 mL) at 5° C.The yellow precipitate was filtered off, washed with water and dried invacuum (3.95 g, 98%).

B. To a solution of the product obtained above (2.0 g, 10 mmol) in THF(300 mL) was added dropwise a solution of hydrazine hydrate (1.33 g, 26mmol) in THF (50 mL) at 65° C. and then the mixture was stirred for 30minutes. The solvent was evaporated in vacuum and the crude product wasrecrystallized from ethanol to give the title compound as a brownishyellow powder (0.971 g, 88%); MS (m/z, ES+): 233 (M+1, 100%).

Example 25 Preparation of4-[(2-methyl-5-nitrophenyl)hydrazono]4H-pyrazole-3,5-diamine

A. To a solution of 2-hydroxymethylaniline (3.04 g, 0.02 mol) in 2 N HCl(80 mL) was added a solution of sodium nitrite (1.65 g, 24 mmol) inwater (20 mL) at 5° C. The resulting reaction mixture was stirred for 10minutes before it was added dropwise to a solution of malononitrile(1.58 g, 24 mmol) and sodium acetate (17 g) in water (150 mL) at 5° C.The yellow precipitate was filtered off, washed with water and dried invacuum (4.51 g, 98%) and used without purification.

B. To a solution of the product obtained above (2.56 g, 11 mmol) in THF(300 mL) was added dropwise a solution of hydrazine hydrate (0.82 g,16.5 mmol) in THF (50 mL) at 65° C. and then the mixture was stirred for30 minutes. The solvent was evaporated in vacuum and the crude productwas recrystallized from ethanol to give the title compound as a orangepowder (2.77 g, 96%); MS (m/z, ES+): 262 (M+1, 100%).

Example 26 Preparation of4-[(4-fluoro-2-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine

4-Fluoro-2-(morpholin-4-yl)methylphenylamine (208 mg, 0.99 mmol) wasdissolved in 2 N HCl (10 mL). A solution of NaNO₂ (79 mg) in water (2.5mL) was added at 0° C. and the clear solution was stirred for 15 minutesand added dropwise to the cooled (0° C.) solution of malononitrile (72mg, 1.04 mmol) in water:NaOAc (2.3 g) (5 mL) with stirring. The brightyellow solid was filtered off, dried in vacuum, and then dissolved inether:THF mixture 3:1 (25 mL). Hydrazine hydrate (100 μL) was added inone portion at ambient temperature. The solution was then heated at 40°C. for 5 minutes, and the solvents were evaporated. The deep orange oilobtained was dissolved in ethyl acetate:hexane (2:1) and filteredthrough silica gel pad to remove the unreacted hydrazine. The productwas isolated by crystallization from hexane:EtOAc (3:1) (24.5 mg, 8%).The concentrated mother liquor was purified by column chromatography(CH₂Cl₂:MeOH=20:3) to yield the title compound in amount of 188 mg(59.5%); MS (m/z, ES+): 320.3 (M+1, 100%).

Example 27 Preparation of4-[(3-fluoro-4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine

3-Fluoro-4-(morpholin-4-yl)methylphenylamine (210 mg, 1.0 mmol) wasdissolved in 2 N HCl (10 mL). A solution of NaNO₂ (79 mg) in water (2.5mL) was added at 0° C. and the clear solution was stirred for 15 minutesand added dropwise to the cool (0° C.) solution of malononitrile (72 mg;1.04 mmol) in water:NaOAc (2.3 g) (5 mL) with stirring. The brightyellow solid was filtered off, dried in vacuum, and then dissolved inether:THF:EtOH mixture 3:2:1 (40 mL). Hydrazine hydrate (100 μL) wasadded in one portion at ambient temperature. The solution was thenheated at 40° C. for 5 minutes, and the solvents were evaporated. Theresidue was dissolved in ethyl acetate, washed with NH₄Cl solution andseparated organic layer was dried over Na₂SO₄. The title compound (164mg, 81%) was purified by column chromatography (CH₂Cl₂:MeOH=20:3); MS(m/z, ES+): 320.1 (M+1, 100%).

Example 28 Preparation of4-[(3-(morpholin-4-ylmethyl)-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine

3-(Morpholin-4-yl)methyl-5-trifluoromethylphenylamine (145 mg, 0.55mmol) was dissolved in 2N HCl (7 mL). A solution of NaNO₂ (69 mg) inwater (2.5 mL) was added at 0° C. and the clear solution was stirred for15 minutes and added dropwise to the cool (0° C.) solution ofmalononitrile (56 mg) in water:NaOAc (5 mL) with stirring. The productwas extracted with ether (40 mL). To this ether extract hydrazinehydrate (70 μL) was added in one portion at ambient temperature. Thesolution was then heated at 40° C. for 5 minutes, and the solvent wasevaporated. The title compound (168 mg, 83%) was purified by columnchromatography (CH₂Cl₂:MeOH=20:3); MS (m/z, ES+): 370.3 (M+1, 70%).

Example 29 Preparation of{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-5-nitrophenyl}methanol

(3-Amino-5-nitrophenyl)methanol (168 mg, 1.0 mmol) was dissolved in 2 NHCl (7 mL). A solution of NaNO₂ (75 mg) in water (2.5 mL) was added at0° C. and the clear solution was stirred for 15 minutes and addeddropwise to the cool (0° C.) solution of malononitrile (56 mg) inwater:NaOAc (5 mL) with stirring. The product was extracted with ether(40 mL). To this ether extract hydrazine hydrate (80 μL) was added inone portion at ambient temperature. The solution was then heated at 40°C. for 10 minutes, and the solvent was evaporated. The title compoundwas isolated by crystallization from ethyl acetate:hexane in amount of115 mg (41%); MS (m/z, ES+): 278.1 (M+1, 100%).

Example 30 Preparation of3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2-hydroxyethyl)benzenesulfonamide

A. 3-Nitrobenzenesulfonyl chloride (2.22 g) dissolved in 20 mL of THFwas added to a solution of 2-aminoethanol (2.0 g) and tryethylamine (2.0g) in 20 mL of THF. The reaction mixture was kept at ambient temperatureovernight. The solvent was removed and the residue was dissolved inwater (20 mL) and then extracted with EtOAc (2×50 mL). The solvent ofthe organic layer was removed and the residue was dissolved in 50 mL ofEtOH and a catalytic amount of Raney-Nickel was added, followed by theaddition of hydrazine hydrate (2 mL). The reaction mixture was kept atambient temperature under argon overnight, filtered through a celitecake. The solvent of the filtrate was removed yielding 1.1 g of3-amino-N-(2-hydroxyethyl)benzenesulfonamide which was used in the nextstep without further purification.

B. The title compound was prepared following a similar procedure asdescribed in Example 2: 3-Amino-N-(2-hydroxyethyl)benzenesulfonamide(0.55 g), malononitrile (0.8 g) and hydrazine hydrate (0.7 mL) yielded0.251 g of the title compound after purification by columnchromatography; MS (m/z, ES+): 326.1 (M+1).

Example 31 Preparation of4-[(2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine

A. 2H-Benzotriazol-5-ylamine was prepared following the similarprocedure as described in Example 12. 5-Nitro-2H-benzotriazole (1.6 g)yielded 0.35 g of 2H-benzotriazol-5-ylamine. In a manner similar to thatdescribed in Example 2, 2H-benzotriazol-5-ylamine (0.35 g),malononitrile (0.3 g) and hydrazine hydrate (0.5 mL) yielded 0.23 g ofthe title compound after purification by column chromatography. MS (m/z,ES+): 244.2 (M+1, 100%).

B. In a similar manner,4-[(2-methyl-2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared from 2-methyl-2H-benzotriazol-5-ylamine (which was preparedfrom methyl-5-nitro-2H-benzotriazole (2.0 g) in a manner similar to thatdescribed above) (0.24 g), malononitrile (0.2 g) and hydrazine hydrate(0.2 g) to yield 0.181 g. MS (m/z, ES+): 258 (M+1, 100%).

Example 32 Preparation of4-(quinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine

A. In a manner similar to that described in Example5,4-(quinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine was prepared.5-Aminoquinoline (0.35 g), malononitrile (0.3 g) and hydrazine hydrate(0.3 mL) yielded 0.043 g of the title compound after the purification bypreparative TLC (⅓ of the crude product).

B. In a similar manner, the following compounds were prepared:

1. 400 mg of4-[(3-trifluoromethoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared from 3-trifluoromethoxyphenylamine (0.42 g), malononitrile (0.3g) and hydrazine hydrate (0.3 mL). MS (m/z, ES+): 287.1 (M+1, 100%).

2. 350 mg of 4-(quinolin-8-ylhydrazono)-4H-pyrazole-3,5-diamine wasprepared from 8-aminoquinoline (0.35 g), malononitrile (0.3 g) andhydrazine hydrate (0.3 mL). MS (m/z, ES+): 254 (M+1, 100%).

3. 430 mg of 4-(quinolin-3-ylhydrazono)-4H-pyrazole-3,5-diamine wasprepared from 3-aminoquinoline (0.35 g), malononitrile (0.3 g) andhydrazine hydrate (0.3 mL). MS (m/z, ES+): 254 (M+1, 40%).

4. 600 mg of 4-[(6-chloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared from 2-chloro-5-aminopyridine (0.62 g), malononitrile (0.8g) and hydrazine hydrate (0.5 mL).

5. 610 mg of4-[(6-methoxypyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared from 2-methoxy-5-aminopyridine (0.6 g), malononitrile (0.4 g)and hydrazine hydrate (0.5 mL). MS (m/z, ES+): 234.1 (M+1, 100%).

Example 33 Preparation of4-[(4-methoxy-3-(morpholin-4-yl)methylphenyl)hydrazono]-4H-pyrazole-3,5-diamine

A. A solution of 2-bromomethyl-1-methoxy-4-nitrobenzene (1.23 g, 5mmol), triethylamine (0.3 mL) and morpholine (1.0 mL, 11.5 mmol) in 45mL of THF was heated at 60° C. for 30 minutes. The solvent wasevaporated in vacuo. The residue was mixed with water (20 mL) andextracted with ether. Organic layers was separated, dried over MgSO₄ andconcentrated in vacuo to yield a yellow solid (1.222 g, 97%), which wasused in the next step without further purification.

B. To a solution of 4-(2-methoxy-5-nitrobenzyl)morpholine (252 mg, 1.0mmol) in THF:ethanol mixture (1:1) (25 mL) was added a catalyticalamount of Raney-Nickel and hydrazine hydrate (450 mg; 9.0 mmol) and themixture was stirred for 1 hour at ambient temperature, filtered througha Celite/silica gel pad. The filtrate was evaporated to yield the pure4-methoxy-3-morpholin-4-ylmethylphenylamine (149 mg, 67%), which wasused in the next step without purification.

C. An aqueous solution (1 mL) of NaNO₂ (55 mg; 0.79 mmol) was addeddropwise to a stirred solution of4-methoxy-3-morpholin-4-ylmethylphenylamine (149 mg 0.67 mmol) in 2 MHCl (2 mL) cooled in an ice-bath. After 3 minutes, this solution wasadded quickly to a cold solution of malononitrile (47 mg; 0.71 mmol) inaqueous sodium acetate (0.4 g in 5 mL of H₂O). The precipitate wascollected by filtration, washed with water and dried in vacuum (170 mg,85%).

D. To a stirred solution of2-[(4-methoxy-3-(morpholin-4-yl)methylphenyl)hydrazono]malononitrileobtained above (0.57 mmol) in THF (25 mL) was added dropwise a solutionof hydrazine hydrate (50 mg, 1 mmol) in THF (1 mL) at 55° C., and themixture was stirred for 30 minutes. The solvent was removed and thetitle compound (160 mg, 85%) was purified by column chromatographyeluted with MeOH:CH₂Cl₂, 3:1; MS (m/z, ES+): 332.3 (M+1, 20%).

E. In a similar manner as described above, the following compounds wereprepared:

1.4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-(morpholin-4-yl)methylphenol:2-Bromomethyl-4-nitrophenol (1.16 g, 5 mmol), triethylamine (0.3 mL) andmorpholine (1.0 mL, 11.5 mmol) yielded 1.02 g (86%) of2-(morpholin-4-yl)methyl-4-nitrophenol.2-(Morpholin-4-yl)methyl-4-nitrophenol (236.4 mg, 0.984 mmol) andhydrazine hydrate (450 mg, 9.0 mmol) afforded pure4-amino-2-(morpholin-4-yl)methylphenol (187 mg, 91%).4-Amino-2-(morpholin-4-yl)methylphenol (187 mg, 0.9 mmol), malononitrile(66 mg; 1.0 mmol) and hydrazine hydrate (40 mg; 0.8 mmol) yielded 106 mgof the product in 52% yield after purification by column chromatographyeluted with MeOH:CH₂Cl₂, 3:1; MS (m/z, ES+): 318.3 (M+1, 40%).

2. 169 mg of4-[(2,6-dichloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared from 2,6-dichloropyridin-3-ylamine (163 mg, 1.0 mmol),malononitrile (70 mg, 1.06 mmol) and hydrazine hydrate (72 μL, 1.3mmol), 62% yield; MS (m/z, ES+): 272.04 (100%), 274.04 (70%).

3. 96 mg of4-[(3-diethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared from 3-diethylaminomethylphenylamine (336 mg, 1.88 mmol),malononitrile (128 mg, 1.94 mmol) and hydrazine hydrate (144 μL, 2.6mmol) with 17.8% yield; MS (m/z, ES+): 288.15 (M+1, 75%).

4. 170 mg of4-[(3-dimethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine wasprepared from 3-dimethylaminomethylphenylamine (243 mg, 1.62 mmol),malononitrile (108 mg, 1.63 mmol) and hydrazine hydrate (144 μL, 2.6mmol), 40.5% yield; MS (m/z, ES+): 260.14 (M+1, 100%).

5. 102 mg of 4-[(6-fluoropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared from 5-amino-2-fluoropyridine (224 mg, 2.0 mmol),malononitrile (140 mg, 2.12 mmol) and hydrazine hydrate (160 μL, 3.2mmol) with 23% yield; MS (m/z, ES+): 222.06 (M+1, 100%).

6. 449 mg of 4-[(4-methylpyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diaminewas prepared from 4-methylpyridin-3-ylamine (270 mg, 2.5 mmol),malononitrile (170 mg, 2.57 mmol) and hydrazine hydrate (150 μL, 3.0mmol) with 82.7% of yield; MS (m/z, ES+): 218.12 (M+1, 100%).

7. 89 mg of 4-(isoquinolin-5-ylazo)-1-methyl-1H-pyrazole-3,5-diamine wasprepared from 5-aminoisoquinoline (1.0 g), malononitrile (1.0 g) andCH₃NHNH₂.H₂SO₄ (0.5 g, neutralized by 0.3 g of NaOH); MS (m/z, ES+):268.4 (M+1, 100%).

Alternatively, the compounds of the invention may be prepared by themethods disclosed in the following Reaction Schemes

A. Compounds of the invention can be obtained starting fromβ-cyanoketones as illustrated in the following Reaction Scheme 2:

A β-cyanoketone (A) reacts with a diazonium salt in the presence of abase to yield the hydrazono-β-cyanoketone (B) which will react withhydrazine either in EtOH or in THF to afford the aminopyrazole.β-Cyanoketones can either be purchased from a chemical supplier such asAldrich/Sigma and Lancaster or be prepared according to the methodsillustrated below in Reaction Schemes 3 and 4:

B. Compounds of the invention can also be prepared from aminopyrazoles.In this method, the aminopyrazole reacts with the diazonium salt toyield the desired compound of the invention as illustrated in ReactionScheme 5 below:

Aminopyrazoles used in this method can be purchased from a chemicalsupplier such as Aldrich/Sigma and Lancaster. They can also be preparedfrom β-cyanoketones as illustrated in below in Reaction Scheme 6 or theprocedures described in J. Med. Chem., 11, 981 (1968), J. Med. Chem.,11, 984 (1968) and in U.S. Pat. No. 3,341,413. Costanzo, A.; Bruni, F;Auzzi, G.; Selleri, S.; Pecori, L. J. Heterocycl. Chem. 1990, 27, 695.

The following Examples illustrate compounds of the invention as preparedby the foregoing Reaction Schemes.

Example 34 Preparation of4-(isoquinolin-5-ylhydrazono)-5-phenethyl-4H-pyrazol-3-ylamine

To an ice cooled solution of 5-aminoisoquinoline (0.1 g, 0.68 mmol) in 3mL of 4 M H₂SO₄ was added the cooled solution of NaNO₂ (0.08 g, 1.16mmol) in 0.5 mL of water. This diazonium salt was then added into asolution of 3-oxo-5-phenylpentanenitrile (0.1 g, 0.58 mmol) and NaOActrihydrate (3.3 g, 24.3 mmol) in a mixture of 3 mL of AcOH and 3 mL ofwater. The solid residue was collected by filtration, dried and thenredissolved in 5 mL of ethanol and treated with hydrazine hydrate (0.2mL). After 2 hours at 45° C., the solvents were removed and the residuewas purified by column chromatography (CHCl₃:MeOH=6:1) to yield 30 mg ofthe title compound. MS (m/z, ES+): 343 (M+1).

Example 35 Preparation of5-but-3-enyl-4-(quinolin-6-ylhydrazono)-4H-pyrazol-3-ylamine

A. A mixture of 6-aminoquinoline (173 mg, 1.2 mmole) in 1.4 mL of waterwas cooled in an ice bath. The solution was acidified with conc. HCl(0.6 mL, 7.2 mmole). A solution of NaNO₂ (99 mg, 1.44 mmole) in 0.5 mLof water was then added. The diazonium mixture was added to a solutionof 1-cyano-5-hexen-2-one (123 mg, 1 mmole) and NaOAc trihydrate (979 mg,7.2 mmole) in a DMF-water mixture. From this reaction, 291 mg of a darkbrown solid was obtained, which was then treated with hydrazine (1mmole) in hot ethanol. After the reaction was complete, the ethanol wasevaporated and diethyl ether was added. A brown powder product wasisolated by filtration. The crude material was purified by columnchromatography (CH₂Cl₂:MeOH=25:1) to yield 80 mg (27%) of the titlecompound as an orange powder. MS (m/z, ES+): 293 (M+1, 100%); ¹H NMR(ppm, 300 MHz, DMSO-d₆-CDCl₃) δ 11.60 (br s, 1H), 8.75 (d, 1H), 8.22 (d,1H), 8.02-8.16 (m, 2H), 7.97 (d, 1H), 7.40 (m, 1H), 6.55 (br s, 2H),5.85 (m, 1H), 5.03 (dd, 1H), 4.92 (d, 1H), 2.92 (t, 2H), 2.00 (t, 2H).

B. In a similar manner,5-but-3-enyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine was preparedfrom 3-aminopyridine (113 mg, 1.2 mmole) and 1-cyano-5-hexen-2-one (123mg, 1 mmole). The crude material was pruified by preparative TLC(CH₂Cl₂:MeOH=21:1) to yield 131 mg (54%) of the title compound as anorange powder. MS (m/z, ES+): 243 (M+1, 100%); ¹H NMR (ppm, 300 MHz,DMSO-d₆) δ 11.68 (br s, 1H), 8.89 (s, 1H), 8.46 (m, 1H), 7.96 (d, 1H),7.46 (dd, 1H), 7.19 (brs, 2H), 5.87 (m, 1H), 5.07 (dd, 1H), 4.96 (d,1H), 2.84 (br m, 2H), 2.46 (t, 2H).

C. In a similar manner,5-but-3-enyl-4-[(3-nitrophenyl)hydrazono]4H-pyrazol-3-ylamine wasprepared from 3-nitroaniline (166 mg, 1.2 mmole) and1-cyano-5-hexen-2-one (123 mg, 1 mmole) with NaOAc (979 mg, 7.2 mmole)according to a procedure similar to Example 2. The crude material waspurified by a prepreparative TLC (CH₂Cl₂:MeOH=21:1) to yield 175 mg(61%) of the title compound as an orange powder. MS (m/z, ES+): 287(M+1, 100%); ¹H NMR (ppm, 300 MHz, DMSO-d₆-CDCl₃) δ 11.60 (br s, 1H),8.38 (s, 1H), 7.99 (m, 1H), 7.57 (t, 1H), 6.64 (br s, 2H), 5.84 (m, 1H),5.03 (d, 1H), 4.92 (d, 1H), 2.88 (m, 2H), 2.48 (m, 2H).

Example 36

The compounds described in this example were prepared using thefollowing procedure: A solution of 3-fluoroaniline (777 mg, 7 mmole)dissolved in 10.5 mL of water was cooled in an ice bath and acidified bythe addition of 1.75 mL of conc. HCl (˜18 mmole). The solution of NaNO₂(665 mg, 9.6 mmole) in 2.8 mL of water was slowly added to the mixture.Total volume of the solution reached 15.05 mL. This mixture was stirredin a salt ice bath for 15 minutes. The resulting diazonium solution wasthen aliquoted (2.15 mL each) into several solutions containing one ofthe β-cyanoketones (1.3 mmole) indicated below and NaOAc trihydrate (410mg, 3 mmole) in 3 mL of H₂O:DMF (1:2). The mixture was stirred atambient temperature for 1 hour and the resulting yellow precipitate wasisolated by filtration, washed with excess water, and dried in vacuoovernight to provide the desired product. A suspension of the desiredproduct (0.5 mmole) in 2 mL of ethanol was heated to 80° C. A solutionof hydrazine hydrate (40 μL, 0.75 mmole) in 1 mL of ethanol was slowlyadded to the suspension. A clear dark coloured solution was generallyobserved. The reaction mixture was then refluxed for 1 hour. After thereaction was complete, the solvent was evaporated. The products wereisolated as yellow solids either by precipitation with ether-hexanes orby preparative TLC.

1. 4-[(3-Fluorophenyl)hydrazono]-5-m-tolyl-4H-pyrazol-3-ylamine wassynthesized from 3-oxo-3-m-tolylpropionitrile to yield 105 mg of theproduct. MS (m/z, ES+): 297.1 (18%), 296.1 (M+1, 92%).

2. 4-[(3-Fluorophenyl)hydrazono]-5-p-tolyl-4H-pyrazol-3-ylamine wassynthesized from 3-oxo-3-p-tolylpropionitrile to yield 66 mg of theproduct. MS (m/z, ES+): 297.1 (23%), 296.1 (M+1, 100%).

3. 5-(3-Chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylaminewas synthesized from 3-oxo-3-(3-chlorophenyl)propionitrile to yield 25mg of the product. MS (m/z, ES+): 319.1 (9%), 318.1 (35%), 317.1 (21%),316.1 (M+1, 95%).

4. 5-(4-Chlorophenyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylaminewas synthesized from 3-oxo-3-(4-chlorophenyl)propionitrile to yield 43mg of the product. MS (m/z, ES+): 318.1 (16%), 317.1 (12%), 316.1 (M+1,46%).

5.4-[(3-Fluorophenyl)hydrazono]-5-(3-trifluoromethylphenyl)-4H-pyrazol-3-ylaminewas synthesized from 3-oxo-3-(3-trifluoromethylphenyl)propionitrile toyield 101 mg of the product. MS (m/z, ES+): 351.1 (20%), 350.1 (M+1,100%).

6.4-[(3-Fluorophenyl)hydrazono]-5-(4-trifluoromethoxyphenyl)-4H-pyrazol-3-ylaminewas synthesized from 3-oxo-3-(4-trifluoromethoxyphenyl)propionitrile toyield 38 mg of the product. MS (m/z, ES+): 367.1 (23%), 366.1 (M+1,100%); ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 12.34 (br. s, 1H), 8.56 (s, 1H),8.40 (m, 1H), 7.90-7.26 (m, 7H), 7.17 (m, 1H).

7.4-[(3-Fluorophenyl)hydrazono]-5-(4-methoxyphenyl)-4H-pyrazol-3-ylaminewas synthesized from 3-oxo-3-(4-methoxyphenyl)propionitrile to yield 44mg of the product. MS (m/z, ES+): 313.2 (20%), 312.1 (96%); ¹H NMR (ppm,200 MHz, DMSO-d₆) δ 12.26 (br s, 1H), 8.05 (d, 2H), 7.77-7.37 (m, 3H),7.36-6.79 (m, 5H), 3.80 (s, 3H).

8. 4-[(3-Fluorophenyl)hydrazono]-5-furan-2-yl-4H-pyrazol-3-ylamine wassynthesized from 3-oxo-3-furan-2-ylpropionitrile to yield 90 mg of theproduct. ¹H NMR (ppm, DMSO-d₆) δ 12.21 (br s, 1H), 7.82 (s, 1H),7.72-7.42 (m, 3H), 7.37 (br s, 1H), 7.16 (m, 1H), 7.07 (m, 1H), 6.66 (s,1H).

9.4-[(3-Fluorophenyl)hydrazono]-5-(2-methylfuran-3-yl)-4H-pyrazol-3-ylaminewas synthesized from 3-oxo-3-(2-methylfuran-3-yl)propionitrile to yield101 mg of the product. ¹H NMR (ppm, DMSO-d₆) δ 12.05 (br s, 1H),7.75-7.42 (m, 4H), 7.38 (br s, 2H), 7.12 (m, 1H), 6.95 (s, 1H), 2.52 (s,3H).

10. 4-[(3-Fluorophenyl)hydrazono]-5-phenyl-4H-pyrazol-3-ylamine wassynthesized from 3-oxo-3-phenylpropionitrile to yield 58 mg of theproduct. MS (m/z, ES+): 282 (M+1, 100%).

11. 4-{5-Amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-yl}benzoicacid methyl ester was synthesized from 4-(1-oxo-but-3-ynyl)benzoic acidmethyl ester to yield 29 mg of the product. ¹H NMR (ppm, DMSO-d₆) δ□12.45 (br s, 1H), 8.30 (d, 2H), 8.10 (d, 2H), 7.90-7.30 (m, 5H), 7.20(m, 1H), 3.90 (s, 3H).

Example 37

The compounds described in this example were prepared by the followingprocedure: Sodium hydride (800 mg, 60% in oil, 20 mmol) was weighed intoa 200 mL flask under argon. Freshly distilled anhydrous toluene (55 mL)was introduced into the flask and the slurry was cooled to 15° C.t-Butyl cyanoacetate (5.6 g, 40 mmole) was then slowly added to thissuspension. Production of gas was observed and a white cloudy mixturewas obtained. A solution of phenylmethyleneacetyl chloride (3.4 g, 20mmole) in 5 mL of anhydrous toluene was added to the mixture. After thereaction was stirred at ambient temperature for 30 minutes, a yelloworange mixture was observed, which became a clear orange solution after1 hour. The mixture was stirred at ambient temperature overnight. Thecloudy solution was worked up by the addition of a mixture of 100 mL ofether and 20 mL of water. The organic phase was separated and washedonce with diluted HCl solution and dried over anhydrous Na₂SO₄, filteredand evaporated in vacuo to afford a yellow oil.

The obtained yellow oil was then dissolved in 120 mL of anhydroustoluene and 4-toluenesulfonic acid (380 mg, 2 mmol) was added. After itwas refluxed for 4 hours, TLC showed that more than 50% of de-protectionoccurred. The reaction mixture was then mixed with 100 mL of ether,washed with the acidified water, dried over anhydrous Na₂SO₄ andfiltered. After the solvent was evaporated, the oil was purified bycolumn chromatography (hexane:CH₂Cl₂=1.5:1) to yield 1.1 g of thedesired compound as a white solid. MS (m/z, ES−): 173 (M, 13), 172 (M−1,100).

The solution of substituted aniline (0.5 mmole) in 0.5 mL of watercooled in an ice bath was acidified with conc. HCl (0.14 mL, 1.7 mmole).A solution of NaNO₂ (51 mg, 0.74 mmole) in 0.25 mL of water was thenadded slowly. The mixture was stirred at 0 to −5° C. for 30 min. Thisdiazonium solution was then added to a mixture of the compound obtainedabove (118 mg, 0.68 mmole) and NaOAc trihydrate (231 mg, 1.7 mmole) in 2mL of DMF:H₂O (1:1) mixture. The product, as a yellowish solid,precipitated instantly, was collected by filtration and dried in vacuo.

The product obtained above (0.3 mmole) was weighed into a 10 mL flaskand dissolved in 2 mL of ethanol. The solution was stirred and heated to70° C. A solution of hydrazine hydrate (18 mg, 0.36 mmole) in 1 mL ofethanol was added dropwise. A clear orange solution was obtained. Thesolution was refluxed for 2 hours. The solvent was then evaporated invacuo and the crude material was purified by preparative TLC.

1. 4-[(3-Fluorophenyl)hydrazono]-5-phenethyl-4H-pyrazol-3-ylamine wassynthesized from 3-fluoroaniline to yield 9 mg of the product. MS (m/z,ES+): 310.2 (M+1, 100%).

2. 4-[(3-Chlorophenyl)hydrazono]-5-phenethyl-4H-pyrazol-3-ylamine wassynthesized from 3-chloroaniline to yield 13 mg of the product. ¹H NMR(ppm, DMSO-d₆) δ 11.72 (br s, 1H), 7.80-7.59 (m, 2H), 7.46 (m, 1H),7.40-7.00 (m, 8H), 3.18-2.90 (m, 4H).

3. 4-[(3,5-Difluorophenyl)hydrazono]-5-phenethyl-4H-pyrazol-3-ylaminewas synthesized from 3,5-difluoroaniline to yield 67 mg of the product.¹H NMR (ppm, DMSO-d₆) 11.77 (br. s, 1H), 7.55-7.00 (m, 10H), 3.17-2.92(m, 4H).

Example 38 Preparation of5-(4-methoxybenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine

To a warm suspension of4-(4-methoxyphenyl)-3-oxo-2-(phenylhydrazono)butyronitrile (1 g, 3.4mmol) in ethanol was slowly added a solution of hydrazine hydrate (204mg, 4.08 mmol) in 10 mL of ethanol. The solution was heated to refluxand a brownish clear solution was obtained. After 2 hours of reflux, thesolvent was removed in vacuo. The obtained oil was dissolved withminimum amount of isopropanol, and a yellow powder was precipitated bythe addition of water. The title compound was isolated by filtration ina yield of 560 mg. The filtrate was further purified by columnchromatography (CH₂Cl₂:MeOH=15:1) and an additional 370 mg of the titlecompound was obtained. The total yield was 92%. MS (m/z, ES+): 308 (M+1,100%); ¹H NMR (ppm, CDCl₃) δ 7.77 (m, 2H), 7.43 (m, 2H), 7.38 (m, 1H),7.21 (d, 2H), 6.86 (d, 2H), 5.41 (br s, 2H), 4.30 (s, 2H), 3.79 (s, 3H).

Example 39 Preparation of5-phenyl-4-(phenylhydrazono)-4H-pyrazol-3-ylaminez

The title compound was prepared using 124 mg (0.5 mmol) of3-oxo-3-phenyl-2-(phenylhydrazono)propionitrile. Hydrazine hydrate wasadded to a solution of 3-(phenylhydrazono)pentane-2,4-dione in ethanol.Precipitate formed in the reaction tube approximately 1.5 hours afterthe addition of hydrazine hydrate. The resulting solid was isolated byfiltration, washed with ethanol, and dried to yield 31 mg of the titlecompound as a yellow solid (24%). ¹H NMR (ppm, DMSO-d₆) δ 6.3 (br s,2H), 7.25-7.55 (m, 6H), 7.75 (d, 2H), 8.0-8.20 (m, 2H), 12.10 (s, 1H);IR (cm⁻¹, KBr pellet): 3376 (w), 3269 (w), 3170 (m), 3082 (m), 3025 (m),2956 (m), 2847 (m), 1625 (s), 1590 (m), 1577 (m), 1511 (s), 1492 (m),1481 (m), 1457 (m), 1447 (m), 1397 (s), 1350 (s), 1303 (w), 1285 (w),1210 (w), 1171 (w), 1070 (w), 975 (m), 916 (w), 808 (w), 775 (m), 762(m), 729 (m), 686 (s), 664 (w), 578 (m); MS (m/z, ES+): 265.2 (M+2, 1%),264.2 (M+1, 5%).

Example 40 Preparation of5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine

A. A solution of 3-fluoroaniline (1.67 g, 15 mmole) in 17 mL of water,acidified with 3.75 mL of conc. HCl (45 mmole) in an ice bath, wastreated with NaNO₂ (1.35 g, 19.5 mmole). The diazonium solution was thenadded to the solution of4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-oxobutyronitrile (2.28 g, 10mmole) with NaOAc (6.12 g, 45 mmole) in DMF/water mixture (30:35 mL).From this reaction, 3.4 g of2-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isoindole-1,3-dione,as a yellow powder, was obtained, which was then treated with hydrazine(22 mmole) portionwise in hot ethanol. After the reaction was completed,a few grams of silica gel was mixed and the solvent was evaporated. Thepowdery residue was purified by column chromatography(CH₂Cl₂:MeOH:NH₃.H₂O=600:150:6) to yield 1.5 g (61%) of the titlecompound as an orange powder. ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 7.40-7.70(m, 3H), 7.12 (m, 1H), 7.00 (br s, 2H), 4.01 (s, 2H).

B. In a similar manner,2-{5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isoindole-1,3-dionewas prepared.

Example 41 Preparation of3-({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)acrylicacid

A. 5-Aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (60mg, 0.25 mmole) was dissolved in 3 mL of anhydrous DMF. To this solutionwas added triethylamine (0.51 mmole, 52 mg) and then a solution ofmaleic anhydride (30.2 mg, 0.31 mmole) in 1 mL of DMF. The reactionmixture was stirred at ambient temperature for 30 minutes and thenworked up by the addition of saline and ethyl acetate. The mixture wasacidified with 1 mL of 1.5 M HCl. The aqueous phase was extracted withethyl acetate. The combined organic layer was washed with saline threetimes and dried over anhydrous MgSO₄. The solution was then filtered,concentrated and purified by preparative TLC (CH₂Cl₂:MeOH:trace aceticacid=6:1) to yield 58 mg of the title compound as a yellow powder. MS(m/z, ES−): 331 (M−1, 100%); ¹H NMR (ppm, 300 MHz, DMSO-d₆) □δ 11.90 (brs, 1H), 7.35-7.70 (m, 3H), 7.30 (br s, 2H), 6.12 (d, 1H), 5.70 (d, 1H),4.52 (s, 2H).

B. In a similar manner,N-{5-amino-4-[(3-fluorophenyl)hydrazono]4H-pyrazol-3-ylmethyl}nicotinamidewas prepared by reacting5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (60 mg,0.25 mmole) with nicotinoyl chloride hydrochloride (46.3 mg, 0.26mmole). The reaction was worked up by the addition of saline and ethylacetate. The crude material was purified by preparative TLC(CH₂Cl₂:MeOH=9:1) to yield 36 mg (41%) of the title compound as a yellowpowder. MS (m/z, ES+): 340 (M+1, 100%); ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ11.80 (br s, 1H), 9.01 (br s, 2H), 8.70 (d, 1H), 8.20 (d, 1H), 7.30-7.70(m, 4H), 6.85-7.25 (m, 3H), 4.70 (br s, 2H).

C. In a similar manner,N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}succinamicacid was prepared by reacting5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (60 mg,0.25 mmole) with succinic anhydide (40 mg, 0.4 mmole). The reaction wasworked up by the addition of aqueous ammonium chloride solution andethyl acetate. The crude material was purified by preparative TLC(CH₂Cl₂:CH₃OH:H₂O:HOAc=210:21:1.6:0.8) to yield 45 mg (51%) of the titlecompound as a yellow powder. MS (m/z, ES−): 333 (M−1, 42%); ¹H NMR (ppm,300 MHz, DMSO-d₆) δ 8.23 (br s, 1H), 7.35-7.63 (m, 3H), 6.83-7.20 (m,3H), 4.42 (s, 2H), 2.33 (m, 4H).

Example 42 Preparation of1-[3-({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)acryloyl]pyrrolidine-2-carboxylicacid methyl ester

To a suspension of L-proline methyl ester hydrochloride (200 mg, 1.21mmole) in 8 mL of ethylene glycol dimethyl ether was added triethylamine(244 mg, 2.4 mmole). The white cloudy mixture was stirred at ambienttemperature for 20 min, and was then treated with maleic anhydride in 1mL of diethyl ether. After 1 hour, the reaction mixture was filtered.The filtrate was mixed with a solution of N-hydroxysuccinimide (172 mg,1.5 mmole) in ethylene glycol dimethyl ether, and then DCC (412 mg, 2mmole) was added. The reaction mixture was stirred at ambienttemperature overnight. After filtration, the solution of the NHS esterwas added in 4 mL portions to a solution of5-(aminomethyl)-4-(3-fluorophenylhydrazono)-3-amino-4H-pyrazole (60 mg,0.25 mmole) and triethylamine (0.51 mmole, 52 mg) in 4 mL of DMF at 45°C. After stirring at ambient temperature for 45 minutes, the reactionwas quenched by the addition of saline and ethyl acetate. The ethylacetate extracts were concentrated and the resulting crude material waspurified by preparative TLC (CH₂Cl₂:CH₃OH=12:1) to yield 44 mg (38%) ofthe title compound as a yellow powder. MS (m/z, ES+): 444 (M+1, 56%),445 (M+2, 13%); ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 11.92 (br s, 1H), 8.80(br s, 1H), 7.35-7.62 (m, 3H), 7.10 (d, J=14.8 Hz, 1H), 7.09 (br s,NH₂), 6.90 (d, J=14.8 Hz, 1H), 4.56 (dd, J=8.5 Hz, 1H), 4.36 (dd, J=8.5,4.0 Hz, 1H), 3.66 (m, 1H), 3.60 (s, OCH₃), 3.45 (m, 1H), 3.34 (m, 1H),2.17 (m, 1H), 1.75-2.00 (m, 3H).

Example 43 Preparation of1-[({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)methyl]pyrrolidine-2-carboxylicacid methyl ester

A. Preparation of N-benzyloxycarbonylmethylpyrrolindine-2-carboxylicacid methyl ester: A mixture of L-proline methyl ester (2.7 g, 16mmole), K₂CO₃ (4.9 g, 35.5 mmole) and benzyl 2-bromoacetate (3.6 g, 16mmole) in 18 mL of toluene was heated to 86° C. for 5 hours. The milkysuspension was then cooled to ambient temperature and treated withaqueous NaHCO₃ and ethyl acetate. The collected organic phase wasextracted with 10% HCl. The aqueous phase was made basic to pH 10 withK₂CO₃ and extracted with ethyl acetate. After washing with saline, theorganic solution was dried over Na₂SO₄, filtered and evaporated todryness. A pale brown liquid was obtained in a yield of 2.5 g (59%). MS(m/z, ES+): 278 (M+1, 100%); ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 7.36 (m,5H), 5.10 (s, 2H), 3.60 (d, J=17 Hz, 1H), 3.57 (s, OCH₃), 3.52 (dd, 1H),3.49 (d, J=17 Hz, 1H), 3.00 (m, 1H), 2.67 (dd, 1H), 2.02 (m, 1H),1.65-1.90 (m, 3H).

B. Preparation of NHS ester of N-carboxymethylpyrrolindine-2-carboxylicacid methyl ester: N-Benzyloxycarbonylmethyl-pyrrolindine-2-carboxylicacid methyl ester (534 mg, 2 mmole) and Pd/C (10%, 8.9 mg) in 2 mL ofethanol was stirred under H₂ atmosphere for 4 hours. Acetic acid (3drops) was then added. After the reaction, the solution was filteredthrough a celite plug. The solvent was evaporated in vacuo and theresidue was mixed with N-hydroxysuccinimide (276 mg, 2.5 mmole) in 5 mLof ethylene glycol dimethyl ether. To this mixture was added DCC (515mg, 2.5 mmole) in 3 mL of ethylene glycol ether. After being stirred atambient temperature overnight, the reaction mixture was filtered. Thefiltrate was used directly in the next reaction.

C. The NHS ester solution, prepared above, was added in 3 mL portions toa solution of5-(aminomethyl)-4-(3-fluorophenylhydrazono)-3-amino-4H-pyrazole (117 mg,0.5 mmole) and triethylamine (1 mmole, 101 mg) in 7 mL of DMF at 45° C.After stirring for 45 minutes at ambient temperature, the reaction wasworked up by the addition of saline and ethyl acetate. The ethyl acetateextracts were concentrated in vacuo and the crude material was purifiedby column chromatography (CH₂Cl₂:CH₃OH=15:1) to yield 120 mg (31%) ofthe title compound as a yellow powder. MS (m/z, ES+): 404 (M+1, 100%);¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 11.80 (brs, 1H), 8.10 (brs, 1H),7.30-7.60 (m, 3H), 7.01 (m, 1H), 6.95 (br s, NH2), 4.44 (dd, J=15.0, 5.6Hz, 1H), 4.29 (dd, J=15.0, 3.9 Hz, 1H), 3.45 (s, 3H), 3.14-3.38 (m, 2H),2.95 (d, 1H), 2.78 (m, 1H).

Example 44 Preparation of1-[({5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)methyl]pyrrolidine-2-carboxylicacid

1-[({5-Amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)-methyl]pyrrolidine-2-carboxylicacid methyl ester (80 mg, 0.20 mmole) was dissolved in 1.5 mL of 95%ethanol with KOH (19.7 mg (85%), 0.29 mmole). The solution was heated at76° C. for 1 hour. The reaction was quenched by the addition of 1 mL ofwater and then acidified to pH 3 with 1.5 M HCl. The solution wasevaporated to dryness together with 2-PrOH and silica gel. The resultingpowder was then placed onto a silica gel column. The crude material waspurified by column chromatography (CH₂Cl₂:MeOH:H₂O:HOAc=240:60:4.7:2.2)to yield 70 mg of the title compound as a yellow powder. MS (m/z, ES−):388 (M−1, 100%); ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 8.77 (br s, 1H),7.35-7.60 (m, 3H), 7.09 (m, 1H), 6.99 (br s, 2H), 4.50 (m, 2H), 3.31 (m,1H), 3.01 (m, 2H), 2.29 (m, 1H), 2.05 (m, 1H), 1.93 (m, 1H), 1.72 (m,1H), 1.50-1.61 (m, 2H).

Example 45 Preparation ofN-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}methanesulfonamide

Methanesulfonyl chloride was reacted with5-(aminomethyl)-4-(3-fluorophenylhydrazono)-3-amino-4H-pyrazole (60 mg,0.25 mmole) in DMF at ambient temperature to yield 43 mg (52%) of thetitle compound. ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 11.49 (br s, 1H),7.20-7.50 (m, 3H), 6.70-7.10 (m, 2H), 6.45 (br s, NH2), 4.40 (d, 2H),2.79 (s, 3H, CH₃).

Example 46 Preparation of4-[(3-fluorophenyl)hydrazono]-5-morpholin-4-ylmethyl-4H-pyrazol-3-ylamine

To a mixture of5-(aminomethyl)-4-(3-fluorophenylhydrazono)-3-amino-4H-pyrazole (60 mg,0.25 mmole) and triethylamine (71 μL, 0.512 mmole) in 3 mL of anhydrousDMF was added solid di(2-tosyloxyethyl)ether (108 mg, 0.25 mmole). Thereaction was heated at 87° C. for 5-6 hours, and was then worked up bythe addition of saline and ethyl acetate. The crude material waspurified by preparative TLC (CH₂Cl₂:CH₃OH=15:1) to yield 13 mg of thetitle compound as a yellow powder. MS (m/z, ES+): 305 (M+1, 100%); ¹HNMR (ppm, 300 MHz, DMSO-d₆) δ 7.53 (m, 1H), 7.40 (m, 2H), 7.03 (m, 1H),6.45 (br s, 2H), 3.97 (s, 2H), 3.74 (m, 4H), 2.65 (m, 4H).

Example 47 Preparation ofN{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}malonamicacid benzyl ester

A solution of malonic acid monobenzyl ester (1.5 eq, 0.26 mmol) inanhydrous DMF (3 mL) was added to a 10 mL reaction vessel containingPS-carbodiimide (2 eq, 380 mg). The reaction mixture was stirred atambient temperature under argon for 10 minutes before a solution of5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (40 mg,0.17 mmol) in anhydrous DMF (3 mL) was added. The mixture was furtherstirred for approximately 16 hours before it was filtered, washed withDMF (3×3 mL) and concentrated under reduced pressure. The title compoundwas obtained in a yield of 38 mg (55%) as a yellow powder with nofurther purification. MS (m/z, ES+): 411 (M+1, 100%); ¹H NMR (ppm, 300MHz, DMSO-d₆) δ 11.40 (brs, 1H, N—H pyrazole), 8.45 (s, 1H, N—H amide),7.40-7.60 (m, 3H, Ar—H), 7.28-7.35 (m, 5H, Ar—H), 7.05-7.15 (t, 1H,F—Ar—H), 5.15 (s, 2H, benzyl CH₂), 4.47 (s, 1H, CH_(a)H_(b) amide), 4.43(s, 1H, CH_(a)H_(b) amide), 3.35 (2H, CH₂ pyrazole-overlap with H₂O).

Example 48 Preparation of butane-1-sulfonic acid{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}amide

A. A solution of5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (40 mg,0.17 mmol) in anhydrous DMF (3 mL) was added to a 10 mL reaction vesselcontaining PS-DIEA (2.5 eq, 150 mg) and butane-1-sulfonyl chloride (1.1eq, 0.19 mmol) suspended in anhydrous DMF (3 mL). The reaction mixturewas stirred at ambient temperature under argon for approximately 16hours before it was filtered, washed with DMF (3×5 mL) and concentratedunder reduced pressure. The resulting yellow residue was recrystallizedfrom ether to yield 13 mg (22%) of the title compound as a yellowpowder. MS (m/z, ES+): 355 (M+1, 100%).

B. In a similar manner,N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-4-fluorobenzenesulfonamidewas prepared as a yellow residue, which was recrystallized fromdichloromethane to yield 4 mg (6%) of the title compound as a yellowpowder (4 mg, 0.010 mmol, 6% yield). MS (m/z, ES+): 394.06 (M+1, 100%).

Example 49 Preparation of5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine

A. 3,4-Difluoroaniline (2.94 g, 22.8 mmole) was mixed with 25 mL ofwater and cooled in an ice-bath. To this solution was slowly added conc.HCl (5.7 mL, 68.4 mmole). A white precipitation was observed. To thismixture was slowly added a solution of NaNO₂ (2.05 g, 29.6 mmole) in 7mL of water. A pale-yellow clear solution was obtained. The resultingdiazonium solution was then added to a solution of4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-oxobutyronitrile (4.4 g, 19.2mmole) and NaOAc trihydrate (68.4 mmole) in 100 mL of DMF and 60 mL ofwater. The mixture was stirred at ambient temperature for 1 hour. Theproduct was isolated by filtration and dried in vacuo to yield 7.1 g ofa yellow powder.

B. The yellow powder obtained above was dissolved in 190 mL of THF andthe solution was heated to 63° C. To this solution was added asuspension of hydrazine hydrate (22 mmole) in 30 mL of THF. Inapproximately 1 hour a precipitate gradually formed. The mixture wasthen cooled to ambient temperature and the solid was collected byfiltration to yield 4.7 g (66%) of a yellow powder. MS (m/z, ES−): 399(M−1, 100%); ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 11.77 (br s, 1H), 8.79 (brs, NH₂), 7.93 (m, 4H), 7.63 (m, 1H), 7.45 (m, 2H), 5.03 (s, 2H), 4.86(br s, NH₂).

C. The yellow powder obtained in the second step was refluxed in ethanolwith a catalytic amount of toluenesulfonic acid (95 mg, 0.5 mmol). Inapproximately 45 minutes, a clear brownish solution was obtained and asignificant amount of yellow precipitate appeared after an additional 35min. To this mixture was added an additional 16 mmol of hydrazinehydrate. Again the solution became clear brown and then a yellowprecipitate formed. The reaction was refluxed for an additional hour.The mixture was then cooled to 65° C. and the title compound as a yellowpowder was isolated by hot filtration in a yield of 3.6 g. MS (m/z,ES+): 253 (M+1, 24%), 236 (M−NH₃, 22%); ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ8.09 (m, 2H), 7.56 (m, 1H), 6.82 (br. s, NH₂), 3.86 (s, 2H).

Example 50 Preparation ofN-{5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}-2-chloro-6-methylnicotinamide

To a 10 mL reaction vessel containing PS-carbodiimide (2 eq, 175 mg) andHOBt (1.7 eq, 20 mg) was added a solution of 2-chloro-6-methylnicotinicacid (1.5 eq, 0.12 mmol) in anhydrous CH₂Cl₂ (2 mL) and anhydrous DMF(0.2 mL). The reaction mixture was stirred at ambient temperature underargon for 30 minutes before a solution of5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (20mg, 0.079 mmol) in anhydrous DCM (3 mL) and anhydrous DMF (0.7 mL) wasadded. The reaction mixture was further stirred for approximately 16hours before it was filtered, washed with DCM (3×3 mL) and concentratedunder reduced pressure. The title compound was obtained as a yellowpowder (yield 26%). MS (m/z, ES+): 406 (Cl³⁵M+1, 20%), 408 (Cl³⁷M+1,10%).

Example 51 Preparation ofN-{5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}nicotinamide

To a solution of5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine(245 mg, 0.97 mmole) and triethylamine (202 mg, 2 mmole) in 10 mL ofanhydrous DMF was added nicotinoyl chloride (178 mg, 1.0 mmol) in 7 mLof anhydrous DMF. The reaction was stirred at ambient temperature for 1hour, and then mixed with saline and ethyl acetate. The title compoundwas purified by column chromatography (CH₂Cl₂:CH₃OH=13:1) to yield 119mg of the title compound as a yellow powder. MS (m/z, ES−): 356 (M−1,20%); ¹H NMR (ppm, 400 MHz, DMSO-d₆) □δ 11.86 (br s, 1H), 9.04 (brs,1H), 9.01 (s, 1H), 8.67 (d, 1H), 8.19 (d, 1H), 7.71 (dd, 1H), 7.57 (m,1H), 7.47 (m, 2H), 7.11 (br s, 2H), 4.69 (s, 2H).

Example 52 Preparation of5-[(bis-pyridin-3-ylmethylamino)methyl]-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine

A. A 2 mL suspension of5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine(100 mg, 0.397 mmole) and triethylamine (120 μL, 0.86 mmole) was heatedto 66° C. To this orange solution was added dropwise a solution of3-bromomethylpyridine (110 mg, 0.43 mmole) in 1 mL of DMF. The reactionwas stirred at 76° C. overnight, and then mixed with saline and ethylacetate. The crude material was purified by prepreparative TLC(CH₂Cl₂:CH₃OH=10:1) to yield 20 mg of the title compound as a yellowpowder. MS (m/z, ES+): 435 (M+1, 73%), 94 (100%).

B. In a similar manner,5-[(bis-pyridin-2-ylmethylamino)methyl]-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamineand({5-amino-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}ethoxycarbonylmethylamino)-aceticacid ethyl ester were prepared.

Example 53 Preparation of4-[(3,4-difluorophenyl)hydrazono]-5-morpholin-4-ylmethyl-4H-pyrazol-3-ylamine

The mixture of5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine(125 mg, 0.5 mmole) and triethylamine (152 mg, 1.5 mmole) in 5 mL of dryDMF was heated to 87° C. To this solution was added slowlydi(2-tosyloxyethyl)ether (311 mg, 0.75 mmole) in 1 mL of DMF. Thereaction mixture was heated at 87° C. for 1.5 hours, and then worked upby the addition of saline and ethyl acetate. The crude material waspurified by preparative TLC (CH₂Cl₂:CH₃OH=16:1) to yield 23 mg of thetitle compound as a yellow powder. MS (m/z, ES+): 323 (M+1, 100%); ¹HNMR (ppm, 300 MHz, CDCl₃) δ 7.52 (m, 2H), 7.24 (m, 1H), 6.25 (br s, 2H),3.95 (s, 2H), 3.74 (m, 4H), 2.64 (m, 4H).

Example 54 Preparation of5-{[bis-(2-morpholin-4-ylethyl)amino]methyl}-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamineand4-[(3,4-difluorophenyl)-hydrazono]-5-[(2-morpholin-4-ylethylamino)methyl]-4H-pyrazol-3-ylamine

A. To an ice cooled solution of 4-(2-hydroxyethyl)morpholine (1.22 mL,10 mmole) and triethylamine (1.39 mL, 10 mmole) in ethylene glycoldimethyl ether (10 mL) was slowly added MsCl (1.1 g, 10 mmole) in 5 mLof ether. A white precipitate formed immediately. After stirring at 0°C. for 10 minutes and then at ambient temperature for 35 minutes, thereaction mixture was cooled again and quenched by the addition of water.The reaction solution was extracted with diethyl ether and the ethersolution was washed with NaHCO₃ solution and saline, dried over Na₂SO₄,filtered and concentrated in vacuo. The resulting solid residue (380 mg)was used in following reaction without further purification.

B. A solution of5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine(252 mg, 1 mmole), NaI (1.1 mg) and triethylamine (101 mg, 1.0 mmole) in5 mL of DMF was heated to 60° C. To this solution was slowly added themesylate prepared above in 7 mL DMF. The reaction was stirred overnightand then quenched by the addition of saline and ethyl acetate. Theorganic phase was isolated, dried over Na₂SO₄, filtered and concentratedin vacuo. The crude material was purified by column chromatography(CH₂Cl₂:CH₃OH=10:1 to CH₂Cl₂:CH₃OH:NH₃—H₂O=486:65:6). The fractionscontaining product were further purified by preparative TLC. The firsttitle compound was isolated in a yield of 126 mg as a yellow powder. MS(m/z, ES+): 478 (M+1, 26%), 114 (100%), 141 (53%); ¹H NMR (ppm, 400 MHz,DMSO-d₆) δ 7.66 (m, 1H), 7.44-7.61 (m, 2H), 7.15 (br s, 2H), 3.82 (s,2H), 3.49 (t, 8H), 2.61 (t, 4H), 2.41 (t, 4H), 2.33 (t, 8H). The secondtitle compound was isolated in a yield of 33 mg as a yellow powder. MS(m/z, ES+): 366 (M+1, 92%), 236 (100%), 114 (93%); ¹H NMR (ppm, 400 MHz,DMSO-d₆) δ 7.70 (m, 1H), 7.45-7.61 (m, 2H), 6.97 (br s, 2H), 3.79 (t,2H), 3.49 (t, 2H), 3.38 (t, 4H), 2.58 (m, 1H), 2.33 (t, 2H), 2.22 (t,4H).

Example 55 Preparation of5-but-3-enyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine

A. To a suspension of sodium hydride (800 mg 60% in oil, 20 mmole) in 55mL of anhydrous toluene at 10° C., t-butyl cyanoacetate (5.6 g, 40mmole) was added dropwise over 15 min. Hydrogen gas was released and amilky white mixture was obtained. To this mixture was added slowly asolution of 4-pentenoyl chloride (2.4 g, 20 mmole) in 5 mL of toluene.The mixture was stirred at ambient temperature overnight and was thenquenched by the addition of 10 mL of water and 200 mL of diethyl ether.The ether solution was washed with 1.5 M of HCl, dried over anhydrousNa₂SO₄, filtered and evaporated in vacuo to give a liquid residue. Theresidue was then redissolved in 100 mL of anhydrous toluene, mixed withtoluenesulfonic acid (380 mg, 2 mmole), and heated to reflux for severalhours. The reaction solution underwent a color change from clearcolorless to brown red. The reaction mixture was stirred at ambienttemperature overnight, and was quenched by the addition of 10 mL ofwater and 100 mL diethyl ether. The solution was filtered to remove abrown solid and the filtrate was washed with 1.5 M HCl. The aqueousphase was extracted with ether and ethyl acetate. The combined organicsolutions were dried over anhydrous Na₂SO₄, evaporated in vacuo. Thecrude material was purified by column chromatography (CH₂Cl₂) to yield805 mg (33%) of the desired compound as a pale-yellow oil. MS (m/z,ES+): 124 (M+1, 100%).

B. 3,4-Difluoroaniline (75 mg, 0.58 mmole) was mixed in 0.5 mL water andthen acidified with conc. HCl (0.15 mL, 1.8 mmole) in an ice bath. Tothis mixture was slowly added 0.25 mL of an aqueous solution of NaNO₂(52 mg, 0.75 mmole). The diazonium salt was then added to the mixture of3-oxohept-6-enenitrile (86 mg, 0.69 mmole) obtained above and NaOActrihydrate (238 mg, 1.8 mmole) in 3 mL of a mixture of water and DMF(1:1). The resulting yellow brown precipitate was filtered and thentreated with hydrazine hydrate (30 mg, 0.6 mmole) in 4 mL of ethanol atreflux for 3 hours. The solvent was removed in vacuo. The brownishresidue was purified by preparative TLC (CHCl₃:MeOH=20:1) to yield 74 mg(46%) of the title compound as a brown yellow powder. MS (m/z, ES+): 278(M+1, 100%); ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 11.82 (br s, 1H), 7.72 (m,1H), 7.56 (m, 2H), 6.79 (br s, 2H), 5.90 (m, 1H), 5.20-4.80 (m, 2H),2.85 (m, 2H), 2.55 (m, 2H).

Example 56 Preparation of5-but-3-enyl-4-(isoquinolin-5-ylhydrazono)-4H-pyrazol-3-ylamine

A. 5-Aminoisoquinoline (175 mg, 1.2 mmole) was mixed in 1.5 mL of 4 Msulfuric acid in an ice bath. To this mixture was slowly added 0.3 mL ofan aqueous solution of NaNO₂ (80 mg, 1.16 mmole). The resultingdiazonium solution was then added to a mixture of 3-oxohept-6-enenitrile(108 mg, 0.88 mmole) obtained as described in Example 22 and NaOActrihydrate (1.7 g, 12.5 mmole) dissolved in 3 mL of acetic acid and 1.5mL of water. The mixture was extracted with ethyl acetate. The extractswere dried over Na₂SO₄, filtered, and evaporated in vacuo to give asticky residue which was then treated with hydrazine hydrate (36 mg,0.72 mmole) in 10 mL of ethanol at refluxing temperature for 4 hours.The solvent was removed in vacuo and the brownish oil residue obtainedwas purified by preparative TLC (CH₂Cl₂:MeOH=15:1) to yield 55 mg (22%)of the title compound as an orange yellow powder. MS (m/z, ES+): 293(M+1, 100%), 294 (M+2, 19%); ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 9.39 (s,1H), 8.58 (d, 1H), 8.20 (d, 1H), 8.05 (d, 1H), 7.91 (d, 1H), 7.75 (t,1H), 6.79 (br s, 2H), 5.90 (m, 1H), 5.20-4.80 (m, 2H), 2.93 (t, 2H),2.49 (m, 2H).

B. In a similar manner, 5-aminotetrazole (0.1 g, 1.1 mmol) and3-amino-5-tert-butylpyrazole (0.2 g, 1.43 mmol) yielded 21 mg of5-tert-butyl-4-[(1H-tetrazol-5-yl)hydrazono]-4H-pyrazol-3-ylamine. MS(m/z, ES+): 236.

Example 57 Preparation of5-aminomethyl-4-(isoquinolin-5-ylhydrazono)-4H-pyrazol-3-ylamine

5-Aminoisoquinoline (175 mg, 1.2 mmole) was mixed in 1.5 mL 4 M sulfuricacid in an ice bath. To this mixture was added slowly a 0.3 mL ofaqueous solution of NaNO₂ (80 mg, 1.16 mmole). The red diazoniumsolution was then added to the mixture of4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-oxobutyronitrile (200 mg, 0.88mmole) and NaOAc trihydrate (1.7 g, 12.5 mmole) dissolved in a mixtureof 3 mL of acetic acid, 1.5 mL of water and 6 mL of DMF. The resultingbrown precipitate was isolated by filtration to give 281 mg of4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-(isoquinolin-5-ylhydrazono)-3-oxobutyronitrile,in the form of a salt. The solid was then suspended with NaOActrihydrate (108 mg, 0.8 mmole) in 24 mL of ethanol and heated to reflux.Excess hydrazine hydrate was added to the mixture in 4 portions (4×36mg, 2.8 mmole) at intervals of one hour. The suspension became a clearred solution. The solvent was removed in vacuo. The residue was purifiedby column chromatography (CH₂Cl₂:MeOH=10:1) to afford a yellow solid.This material was further purified by preparative TLC(CH₂Cl₂:MeOH:NH₃.H₂O=200:40:2) to yield 18 mg of the title compound asan orange powder. MS (m/z, ES+): 268 (M+1, 90%).

Example 58 Preparation ofN-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}isonicotinamide

To a solution of5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (60 mg,0.256 mmole), DMAP (31.2 mg, 0.256 mmole), and isonicotinic anhydride(70.2 mg, 0.31 mmole) in DMF (4 mL) was added triethylamine (51.7 mg,0.512 mmole). The reaction mixture was stirred at ambient temperaturefor 30 minutes, and then saline and ethyl acetate were added. Theaqueous phase was extracted with ethyl acetate. The organic extractswere dried over Na₂SO₄, filtered and concentrated in vacuo. The crudematerial was purified by preparative TLC to yield 43 mg (50%) of thetitle compound as a yellow powder. ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ11.92 (br s, 1H), 9.15 (br s, 1H), 8.67 (m, 2H), 7.76 (m, 2H), 7.30-7.63(m, 3H), 6.70-7.25 (m, 3H), 4.70 (s, 2H).

Example 59 Preparation of4-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-yl}benzoic acid

A suspension of 3-fluoroaniline (0.364 g, 3.28 mmol) in water (6.5 mL)cooled in an ice/salt bath was acidified with conc. HCl (1 mL, 12 mmol)to give a clear yellow solution. To this solution was added dropwise thecold solution of NaNO₂ (0.277 g in 2 mL of H₂O) while maintaining thereaction temperature below 5° C. The diazonium solution was stirred atice bath temperature for approximately 15 minutes before it was addedportion-wise to a cold mixture of methyl 4-(2-cyanoacetyl)benzoate(0.756 g, 3.72 mmol) and NaOAc (1.62 g) in water (3 mL) and DMF (6 mL).The resulting yellow suspension was stirred at ambient temperature for 1hour. The solid was collected by filtration and washed with excessamount of water and dried in vacuo to yield a yellow solid (0.817 mmol,25%). This yellow solid was refluxed in ethanol (10 mL) and hydrazinehydrate (47 uL, 0.96 mmol) was added. The solution was refluxed for 2hours at which point the reaction mixture was concentrated in vacuo. Theresidue was purified by column chromatography (CHCl₃:CH₃CN:MeOH=20:5:1)to yield a yellow solid (0.297 mmol, 9% overall yield). ¹H NMR (ppm, 300MHz, DMSO-d₆) δ 12.26 (br s, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.40-7.63(m, 5H), 7.17 (t, 1H), 3.86 (s, 3H). The solid (0.048 g, 0.142 mmol) wasrefluxed in ethanol (10 mL) containing ground KOH (0.260 g, 85%) for 4hours and left to stir at ambient temperature overnight. HCl (1.5 M)solution was then added until a pH of 2-4 was achieved. The reactionmixture was concentrated and purified by column chromatography(CH₂Cl₂:MeOH=9:1) to yield the title compound as a yellow-brown powder(0.070 mmol, 50% yield). ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 12.60 (br,1H), 8.25 (d, 1H), 8.05 (d, 1H), 7.40-7.65 (m, 3H), 7.33 (s, 2H), 7.15(t, 1H); MS (m/z, ES−): 324 (100%), 325 (20%).

Example 60 Preparation of5-methyl-4-[(2H-tetrazol-5-yl)hydrazono]-4H-pyrazol-3-ylamine

A. A solution of aminotetrazole (0.1 g, 1.1 mmol) in 4 M sulfuric acid(3.0 mL, 12.0 mmol) was cooled to −5° C. To this mixture was then addeda cooled solution of sodium nitrite (0.08 g, 1.1 mmol) in 0.5 mL ofwater. The solution was then added to a solution of3-amino-5-methylpyrazole (0.2 g, 2.1 mmol) and NaOAc trihydrate (1.5 g,11 mmol) dissolved in a mixture of water (1 mL) and HOAc (3 mL). Afterstirring for 2 hours, water (50 mL) was added and the crude material wasextracted from the aqueous layer three times with ethyl acetate (150mL). The combined ethyl acetate solutions were washed with brine, driedover anhydrous MgSO₄, filtered and evaporated. The crude material waspurified by column chromatography (CHCl₃:MeOH:NH₄OH=3:1:0.005). Theisolated material was then further purified by preparative TLC(CHCl₃:MeOH:NH₄OH=3:1:0.005) to yield 7 mg (3%) of the title compound asa red solid.

B. In a similar manner,5-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-2H-[1,2,3]triazole-4-carboxylicacid was prepared.

Example 61 Preparation of4-(phenylhydrazono)-5-pyridin-2-yl-4H-pyrazol-3-ylamine

A. Ethyl picolinate (10 g, 66.2 mmol) and acetonitrile (4 mL) werepremixed and added into a suspension of potassium tert-butoxide (10.6 g,94.5 mmol) in 200 mL of dry toluene at 80° C. The mixture was stirred atthis temperature overnight. The solid precipitate was collected byfiltration and dried in vacuo. The product was isolated as its potassiumsalt (12 g).

B. To a suspension of aniline (2.0 g, 21.5 mmole) in 30 mL of water wasadded conc. HCl (4.5 mL, 54 mmol) in an ice bath. NaNO₂ (0.8 g, 12.6mmole) dissolved in 2.5 mL of water was added to this mixture slowly.The diazonium solution was then added to the mixture of the potassiumsalt of 3-oxo-3-pyridin-2-yl-propionitrile (2.0 g, 11.0 mmole) obtainedabove and NaOAc trihydrate (10.0 g, 73.5 mmole) dissolved in 50 mL ofwater at 10° C. The precipitate was collected by filtration and thenresuspended in 40 mL of ethanol. Hydrazine hydrate (1.0 g) was addedslowly to this suspension at 80° C. and the mixture was stirred at thistemperature for 2 hours. The title compound was obtained afterrecrystallization from ethanol (1.0 g). MS (m/z, ES+): 265.3 (M+1,100%).

Example 62 Preparation of4-(pyridin-3-ylhydrazono)-5-thiophen-2-yl-4H-pyrazol-3-ylamine

To a suspension of 3-aminopyridine (0.28 g, 2.98 mmole) in water wasadded conc. HCl (1.0 mL, 12 mmol) in an ice bath. NaNO₂ (0.2 g, 3.15mmole) in water was added to this mixture slowly. The diazonium solutionwas then added to the mixture of 3-oxo-3-thiophen-2-ylpropionitrile(0.25 g, 1.65 mmol) and NaOAc trihydrate (5.0 g, 36.7 mmole) dissolvedin 5 mL of water and 2 mL of DMF at 10° C. The precipitate was collectedby filtration and then resuspended in 20 mL of ethanol. Hydrazinehydrate (0.5 g) was added slowly to this suspension at 80° C. and themixture was stirred at this temperature for 3 hours. The solvent wasremoved in vacuo. The title compound was obtained afterrecrystallization from EtOAc/ethanol twice (0.115 g). MS (m/z, ES+):271.2 (M+1, 100%).

Example 63 Preparation of5-(1-methyl-1H-pyrrol-2-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine

A. 1-Methyl-1H-pyrrole-2-carboxylic acid methyl ester (5 g, 35.9 mmol)and CH₃CN (2.5 mL) were premixed and added into a suspension ofpotassium tert-butoxide (5.3 g, 47.2 mmol) in 150 mL of dry toluene at90° C. The mixture was stirred at this temperature overnight. The solidprecipitate was collected by filtration, washed with EtOAc andredissolved in 20 mL of water. The resulting solution was acidified with1 N HCl to approximately pH 1 and was then extracted with EtOAc. Theproduct 3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropionitrile was obtainedafter removal of the solvent (1.9 g).

B. To a suspension of aniline (1.5 g, 16.1 mmol) in 10 mL of water wasadded conc. HCl (4 mL, 48 mmol) in an ice bath. NaNO₂ (1.3 g, 20.5 mmol)dissolved in 5 mL of water was added to this mixture slowly. A portionof this diazonium solution (⅔) was then added to the mixture of3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropionitrile (1.0 g, 6.75 mmol)obtained above and NaOAc trihydrate (10.0 g, 73.5 mmole) dissolved in amixture of 15 mL of water, 10 mL of DMF and 5 mL of acetic acid at 10°C. The precipitate was collected by filtration and dried. It wasresuspended in 50 mL of ethanol. Hydrazine hydrate (1.0 g) was addedslowly to this suspension at 80° C. and the mixture was stirred at thistemperature for 1.5 hours. The solvent was removed and the residue waspurified by column chromatography (CH₂Cl₂:MeOH=20:1). The title compoundwas obtained after recrystallization from Et₂O:hexane (0.5 g). ¹H NMR(ppm, 300 MHz, CDCl₃) δ 12.00 (br s, 1H), 7.69 (d, 2H), 7.40 (t, 2H),7.30 (t, 1H), 6.86 (t, 1H), 6.63 (dd, 1H), 6.29 (dd, 1H), 5.53 (s, 2H),3.79 (s, 3H); FTIR (KBr disk, cm⁻¹): 3367 (s), 1615 (s), 1508 (s), 1475(s), 1451 (s), 1394 (s), 1342 (s), 1312 (s), 1291 (s), 1220 (m), 1197(m), 1164 (m), 1087 (m), 1072 (m), 1017 (m), 956 (m), 802 (w), 773 (m),729 (s), 690 (m), 608 (w), 574 (w); MS (m/z, ES+): 267.2 (M+1, 70);Anal. Calcd for C₁₄H₁₄N₆: C, 63.14; H, 5.30; N, 31.56. Found C, 63.12;H, 5.31; N, 31.42.

C. In a similar manner,5-(1-methyl-1H-pyrrol-2-yl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 3-aminopyridine (0.25 g, 2.66 mmol) to yield 0.21 g ofthe product. MS (m/z, ES+): 268.2 (M+1, 100%).

D. In a similar manner,5-(1-methyl-1H-pyrrol-2-yl)-4-(quinolin-6-ylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 6-aminoquinoline (0.25 g, 1.73 mmol) to yield 85 mg ofthe product. MS (m/z, ES+): 318.3 (M+1, 100%).

Example 64 Preparation of5-(2-morpholin-4-ylethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine

A. A mixture of ethyl 5-bromovalerate (8 g, 38.3 mmole), morpholine(3.67 g, 42 mmole) and triethylamine (4.2 g, 42 mmole) in ethanol (100mL) was heated to reflux overnight. The solution was concentrated toafford a gummy white solid which was mixed with diethyl ether andfiltered to remove the solid. The filtrate was washed with saline (3×50mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 7.1g (87%) of ethyl 5-morpholin-4-ylpentanoate as a pale brown liquid. MS(m/z, ES+): 217 (M+2, 100%), 216 (M+1, 57%).

B. To a suspension of sodium hydride (2 g 60% in oil, 49.7 mmole) in drytoluene (58 mL) at 76° C. was added dropwise neat acetonitrile (2.6 mL,49.7 mmole). Subsequently, a solution of ethyl5-morpholin-4-ylpentanoate (7.13 g, 33.2 mmole) in dry toluene (24 mL)was added dropwise over 30 minutes. The reaction mixture was stirred at76° C. overnight. The solution was then cooled to ambient temperature,the resulting solid was isolated by filtration and washed with tolueneand diethyl ether to afford 5.8 g (75%) of the product,5-morpholin-4-yl-3-oxo-2-(phenylhydrazono)pentanenitrile, as apale-brown powder. MS (m/z, ES+): 211 (M+1, 100%).

C. To a suspension of5-morpholin-4-yl-3-oxo-2-(phenylhydrazono)pentanenitrile (1.2 mmole) in15 mL of diethyl ether was slowly added a solution of hydrazine hydrate(2.4 mmol) in 2 of THF which resulted in a clear red solution. After 2hours, another portion of hydrazine (2.4 mmol) was added at which pointsome yellow precipitate was observed. The reaction was stirred atambient temperature overnight. The solid was collected by filtration,purified by recrystalization from ethanol and dried in vacuo to yield150 mg (41%) of the title compound. MS (m/z, ES+): 301 (M+1, 100%). ¹HNMR (ppm, 300 MHz, DMSO-d₆) δ 11.63 (br s, 1H), 7.67 (m, 2H), 7.44 (m,2H), 7.29 (m, 1H), 6.97 (br s, 2H), 3.55 (m, 4H), 2.93 (m, 2H), 2.66 (m,2H), 2.43 (m, 4H).

Example 65 Preparation of5-(3-Aminopropyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine

A. To a mixture of phthalic anhydride (14.8 g, 100 mmole) and4-aminobutyric acid (10.3 g, 100 mmole) in 150 mL of dry toluene wasadded triethylamine (1.3 mL, 9.3 mmole). The reaction mixture was heatedto reflux in a flask equipped with a Dean Stark trap and condensor.After refluxing for 2.5 hours, the reaction solution was cooled in anice bath which resulted in the formation of a white precipitate. Thesolid was isolated by filtration and washed with 5% HCl (3×80 mL)followed by cold water (2×70 mL). 4-Phthalimidobutyric acid was obtainedas a white powder (16.8 g, 72%). m.p.: 118-118.6° C.

B. To a suspension of 4-phthalimidobutyric acid (16.5 g, 71 mmole) andoxalyl chloride (9.3 g, 73.4 mmole) in 118 mL of dry toluene was slowlyadded a solution of DMF (0.23 mL) in 29 mL of toluene. The evolution ofgas was observed. The mixture was stirred at ambient temperature for 2to 3 hours which resulted in a clear pale yellow solution. The solutionof 4-phthalimidobutyric chloride was used in the following reactionwithout further purification.

C. To a suspension of sodium hydride (3.0 g, 60% in oil, 75 mmole) indry toluene (126 mL) at 15° C. was slowly added t-butyl cyanoacetate(14.1 g, 100 mmole). The generation of hydrogen gas was observed. Thereaction was stirred for 1 hour at which point the solution of4-phthalimidobutyric chloride was introduced over a period of 15 min.The reaction mixture was then stirred at ambient temperature overnight.The reaction was worked up by the addition of water and 1.5 M HCl. Theaqueous layer was extracted with diethyl ether (2×200 mL) and theorganic extracts were washed with saline and dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to afford an oil. The oil wasthen dissolved in dry toluene (200 mL) and toluenesulfonic acid (500 mg,2.6 mmole) was added. The solution was then heated to reflux. A brownresidue was noted to have oiled out of solution. After approximately 2hours, the hot solution was decanted from the reaction flask to separateit from the dark oil by-product. The solution was allowed to cool toambient temperature, at which point more by-product had oiled out ofsolution. The decantation step was repeated. The resulting clearsolution was concentrated in vacuo to afford an oil. This oil wassubjected to column chromatography (CH₂Cl₂:MeOH=100:1) to provide amaterial enriched in the desired product, i.e.,6-phthalimido-3-oxo-hexanenitrile. This material was then mixed withhexanes to yield 5.73 g (31%) of a white powder. MS (m/z, ES+): 257(M+1, 10%), 216 (M+1-CH₃CN, 20%).

D. To an orange red solution of 6-phthalimido-3-oxohexanenitrile (512mg, 2 mmole) and NaOAc trihydrate (1.2 g, 9 mmole) in 16 mL of water:DMF(1:2) was added the pale brown solution of 3-fluoroaniline diazoniumsalt, made from a reaction of 3-fluoroaniline (3 mmole, 333 mg) with0.75 mL of conc. HCl and NaNO₂ (3.6 mmole, 248 mg) in water at −5° C. Ayellow orange powder was instantly formed. The solid was isolated byfiltration and dryed to give 702 mg (93%) of a yellow powder. MS (m/z,ES+): 379 (M+1, 100%). The resulting yellow powder was then treated withhydrazine hydrate (3.4 mmole) in ethanol (15 mL). The suspension washeated to 82° C. for 1 hour. The mixture became a clear orange solutionand then a yellow precipitate was observed. The title compound wasisolated by filtration in a yield of (449 mg, 85%) as a yellow powder.MS (m/z, ES+): 263 (M+1, 50%), 123 (100%).

E. In a similar manner,5-(3-aminopropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine was preparedusing aniline. The crude material was purified by column chromatographyto yield 140 mg (29%) of the title compound. MS (m/z, ES+): 245 (M+1,33%), 105 (100%); ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 7.66 (m, 2H), 7.44(m, 2H), 7.29 (m, 1H), 6.54 (br s, NH2), 2.81 (t, 2H), 2.59 (t, 2H),1.76 (m, 2H).

Example 66 Preparation of4-[(3-fluorophenyl)hydrazono]-5-(3-morpholin-4-yl-propyl)-4H-pyrazol-3-ylamine

A suspension of5-(3-aminopropyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine,obtained in Example 32, (400 mg, 1.53 mmole) and triethylamine (6 mmole)in 10 mL of DMF was heated to 96° C. To this solution was slowly added asolution of ethylene glycol ditosylate (3 mmole) in 10 mL DMF. Thereaction was worked up by the addition of saline and ethyl acetate. Theorganic phase was separated, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude material was purified by columnchromatography and further by preparative TLC. The resulting 34 mg ofoil was dissolved in a minimum amount of diethyl ether and then mixedwith hexanes to yield 22 mg of the title compound as a yellow powder. MS(m/z, ES+): 333 (M+1, 100%).

Example 67 Preparation of5-(4-methoxybenzyl)-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine

A. 3-Aminopyridine (18 g, 0.195 mol) in 221 mL of water was cooled in anice bath with and acidified with conc. HCl (98 mL, 1.2 mol). Thesolution was then treated with NaNO₂ (16.2 g, 0.234 mole) dissolved in60 mL of water at −5° C. The resulting diazonium solution was then addedto a solution of sodium acetate (1.17 mole) and4-(4-methoxyphenyl)-3-oxobutyronitrile (˜0.19 mole) dissolved in 800 mLof water. The yellow precipitate was isolated by filtration and dried invacuo to afford a pale brown powder (24 g, 52%).

B. The powder prepared above was suspended in 350 mL of ethanol andheated to 82° C. Hydrazine hydrate (0.12 mole) was then added slowly.After 2 hours, the reaction solution was concentrated in vacuo and theresulting oil was subjected to column chromatography (CH₂Cl₂:MeOH=20 to15:1). The resulting oil was dissolved in ˜30 mL of i-PrOH and mixedwith 90 mL of water. After cooled in ice, a yellow powder precipitatedfrom solution. The solution was filtered and the resulting solid wasdried to yield 22 g (80%) of the title compound. MS (m/z, ES+): 243(M+1, 100%). ¹H NMR (ppm, 300 MHz, DMSO-d₆) δ 11.68 (br s, 1H), 8.89 (s,1H), 8.45 (m, 1H), 7.95 (m, 1H), 7.44 (m, 1H), 7.16 (brs, 2H), 5.87 (m,1H), 5.06 (dd, 1H), 4.95 (d, 1H), 2.82 (m, 2H), 2.45 (m, 2H, overlappedwith DMSO).

Example 68 Preparation of5-(4-morpholin-4-ylbutyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine

A. The mixture of ethyl 5-bromovalerate (8 g, 38 mmole), morpholine (3.7g, 42 mmole) and triethylamine (4.2 g, 42 mmole) in 100 mL of ethanolwas refluxed overnight. The reaction solution was concentrated, mixedwith diethyl ether, and then filtrated to remove the salt, Et₃NHBr. Thefiltrate was washed with saline, dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to afford 7.1 g (86%) of a colourless oil.

B. To a solution of sodium hydride (2 g, 60% in oil, 49.7 mmol) in drytoluene (60 mL) at 76° C. was added acetonitrile (2 g, 49.7 mmol). Asolution of ethyl 5-(N-morpholino)valerate in 20 mL of toluene was thenadded dropwise. The mixture was stirred at 76° C. overnight. Thesolution was filtered to afford 5.8 g (75%) of the product,7-morpholin-4-yl-3-oxoheptanenitrile, as a white powder.

C. Aniline (419 mg, 4.5 mmole) in 5 mL of water was cooled in an icebath and acidified with conc. HCl (1.1 mL, 13.2 mmol). This mixture wasthen treated with a solution of NaNO₂ (373 mg, 5.4 mmole) in 1.3 mLwater at −5° C. The diazonium salt solution was added a solution ofNaOAc trihydrate (1.8 g, 13.5 mmole) and7-morpholin-4-yl-3-oxoheptanenitrile (3 mmole) dissolved in 15 mL ofwater. The resulting yellow precipitate was isolated by filtration anddried in vacuo to yield 548 mg (58%) of the product,7-morpholin-4-yl-3-oxo-2-(phenylhydrazono)-heptanenitrile, as a paleyellow powder.

D. The powder of7-morpholin-4-yl-3-oxo-2-(phenylhydrazono)-heptanenitrile (510 mg, 1.6mmole) and hydrazine hydrate (3.2 mmole) were suspended in 20 mL ofether:THF (1:1) and stirred at ambient temperature overnight. Water wasadded to the reaction and the mixture was extracted with ethyl acetate.The organic extracts were washed with saline. The volume of the organicsolution was reduced which resulted in the precipitation of a yellowsolid. The solution was filtered to yield 270 mg (51%) of the titlecompound as a yellow powder. MS (m/z, ES+): 329 (M+1, 100%); ¹H NMR(ppm, 300 MHz, DMSO-d₆) δ 11.58 (br s, 1H), 7.66 (m, 2H), 7.44 (m, 2H),7.30 (m, 1H), 6.98 (br s, 2H), 3.51 (m, 4H), 2.79 (m, 2H), 2.20-2.33 (m,5H), 1.72 (m, 2H), 1.47 (m, 2H).

Example 69

The compounds in this Example were prepared according to the followingprocedure: Sodium hydride (320 mg, 60% in mineral oil, 8 mmol) wassuspended in DMF (8 mL). The mixture was cooled to 0° C. and t-butylcyanoacetate (572 mL, 4 mmol) in DMF (1 mL) was added dropwise bysyringe. The reaction mixture was stirred at 0° C. for 30 min. and wasthen cooled to −10° C. with an acetone-ice bath. The acid chloride (4mmol) in DMF (2 mL) was added dropwise by syringe. After the additionwas complete (˜1 hour), the mixture was added into cold water (10 mL)and acidified with dilute HCl (2 N) to pH 2. The precipitate wascollected by filtration and washed with water (2×4 mL) followed byhexane (2×4 mL). The product was either air-dried or dissolved indichloromethane, dried over anhydrous MgSO₄, filtered, and concentratedin vacuo to give the product as a moisture free solid.

The cyanoketone precursor obtained above was dissolved in toluene (10mL) followed by the addition of p-toluenesulfonic acid (10%, 76 mg). Thereaction mixture was stirred at reflux temperature and the progress ofthe reaction was monitored by TLC. After the reaction was complete (˜4hours), the solution was allowed to cool and the solvent was evaporated.The solid obtained in this step was used for the next reaction.

A solution of aniline (91 μL, 1 mmol) in 1 mL of water was cooled in anice bath to 0° C. and was acidified with conc. HCl (300 μL, 3.6 mmol).To the reaction mixture was added a solution of NaNO₂ (90 mg, 1.3 mmol)in 0.5 mL of water. This mixture was then added to a cooled solution ofthe above prepared cyanoketone (1 mmol) and NaOAc trihydrate (340 mg,2.5 mmol) dissolved in 4 mL of a water DMF mixture (3:1). After stirringfor 2 hours, the resulting solid was collected by filtration, washedwith water, and air dried. This material was used in the following stepwithout further purification.

The solid prepared above (˜1 mmol) was dissolved in ethanol (5 mL) andthe solution was heated to 65° C. A solution of hydrazine hydrate (50mg, 1 mmol) in ethanol (2 mL) was then added slowly. The reaction wasrefluxed for 2 hours at which point most of the starting material hadbeen converted to a polar yellow spot as indicated by TLC analysis. Thesolvent was evaporated in vacuo and the resulting crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield thedesired product as a yellow powder.

1. 5-(2-fluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 2-fluorobenzoyl chloride (4 mmol). The product waspurified by precipitation from isopropanol by the addition of water toyield 17 mg (5%) of the compound. ¹H NMR (ppm, 500 MHz, CDCl₃) δ 8.52(t, 1H), 7.77 (d, 2H), 7.48 (t, 2H), 7.40-7.46 (m, 1H), 7.39 (q, 1H),7.33 (t, 1H), 7.23 (dd, 1H), 5.6 (br s, 2H); MS (m/z, ES+): 282.2 (M+1,100%).

2. 5-ethyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine was prepared frompropionyl chloride with the exception that the decarboxylation step wasachieved by treatment with TFA (500 μL) at ambient temperature for 2hours. The product was purified by precipitation from isopropanol by theaddition of water to yield 47 mg (18%) of the compound. ¹H NMR (ppm, 500MHz, CDCl₃) δ 9.5 (br s, 1H), 7.73 (d, 2H), 7.44 (t, 2H), 7.34 (t, 1H),5.47 (br s, 2H), 3.02 (q, 2H), 1.40 (t, 3H); MS (m/z, ES+): 216.2 (M+1,100%).

3. 5-(3,4-dimethoxyphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3,4-dimethoxybenzoyl chloride. The product was isolatedwithout further purification to yield 32 mg (6%) of the compound. ¹H NMR(ppm, 500 MHz, CDCl₃) δ 7.75 (d, 2H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.45(t, 2H), 7.36 (t, 1H), 6.97 (d, 1H), 5.6 (br s, 2H), 3.95 (s, 3H), 3.95(s, 3H); MS (m/z, ES−): 322.3 (M−1, 100%).

4.5-(2-chloro-6-methylpyridin-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 2-chloro-6-methylisonicotinoyl chloride with theexception that the decarboxylation step was achieved by treatment withp-toluenesulfonic acid and TFA (20 μL) at 80° C. for 2 hours. Theproduct was isolated without further purification to yield 49 mg (15%)of the compound. ¹H NMR (ppm, 500 MHz, CDCl₃) δ 7.94 (s, 1H), 7.84 (s,1H), 7.75 (d, 2H), 7.51 (t, 2H), 7.40 (t, 1H), 6.01 (br s, 2H), 2.62 (s,3H); MS (m/z, ES+): 313.3 (Cl³⁵M+1, 100%), 315 (Cl³⁷M+1, 60%).

5.5-(3,5-dimethylisoxazol-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 3,5-dimethylisoxazole-4-carbonyl chloride. The productwas isolated without further purification to yield 44 mg (23%) of thecompound. ¹H NMR (ppm, 500 MHz, CDCl₃) δ 7.69 (d, 2H), 7.44 (t, 2H),7.36 (t, 1H), 5.76 (br s, 2H), 2.52 (s, 3H), 2.37 (s, 3H); MS (m/z,ES+): 283.4 (M+1, 100%).

6. 5-(4-chlorophenoxymethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from (4-chlorophenoxy)acetyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 23 mg(2%) of the compound. MS (m/z, ES+): 328.2 (Cl³⁵M+1, 100%), 330.2(Cl³⁷M+1, 60%), 200.2 (M−117, 80%).

7. 5-(4-chloro-3-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 4-chloro-3-nitrobenzoyl chloride. The crude materialwas purified by column chromatography (CH2Cl2:CH3OH=20:1) to yield 73 mg(5%) of the compound. MS (m/z, ES+): 343.1 (M+1, 100%).

8. 5-(4-chlorobenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from (4-chlorophenyl)acetyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 48 mg(4%) of the compound. MS (m/z, ES+): 312.2 (Cl³⁵M+1, 100%), 314.2(Cl³⁷M+1, 70%).

9. 5-benzhydryl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine was preparedfrom diphenylacetyl chloride. The crude material was purified by columnchromatography (CH₂Cl₂:CH₃OH=20:1) to yield 79 mg (6%) of the compound.MS (m/z, ES+): 354.3 (M+1, 100%).

10. 5-(5-bromopyridin-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 5-bromonicotinoyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 10 mg(1%) of the compound. MS (m/z, ES+): 342.9 (Br⁷⁹M+1, 100%), 344.9(Br⁸¹M+1, 100%).

11. 5-cyclopropyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine was preparedfrom cyclopropanecarbonyl chloride. The crude material was purified bycolumn chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 26 mg (3%) of thecompound. MS (m/z, ES+): 228.3 (M+1, 100%).

12.5-benzo[1,2,5]oxadiazol-5-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from benzo[1,2,5]oxadiazole-5-carbonyl chloride. The crudematerial was purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) toyield 29 mg (3%) of the compound. MS (m/z, ES+): 306.4 (M+1, 100%).

13. 5-(4-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 4-nitrobenzoyl chloride. The crude material was purifiedby column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 8 mg (1%) of thecompound. MS (m/z, ES+): 309.3 (M+1, 100%).

14. 5-(2-chloropyridin-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 2-chloroisonicotinoyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 36 mg(3%) of the compound. MS (m/z, ES+): 299.3 (Cl³⁵M+1, 100%), 301.3(Cl³⁷M+1, 50%).

15. 5-(3-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3-nitrobenzoyl chloride. The crude material was purifiedby column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 27 mg (2%) of thecompound. MS (m/z, ES+): 309.3 (M+1, 100%).

16. 5-benzo[1,3]dioxol-5-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from benzo[1,3]dioxole-5-carbonyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 158mg (13%) of the compound. MS (m/z, ES+): 308.3 (M+1, 100%).

17. 5-(3-bromophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3-bromobenzoyl chloride. The crude material was purifiedby column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 28 mg (2%) of thecompound. MS (m/z, ES+): 342.1 (Br⁷⁹M+1, 100%), 344.1 (Br81M+1, 60%).

18. 5-(3-fluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3-fluorobenzoyl chloride. The crude material was purifiedby column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 32 mg (3%) of thecompound. MS (m/z, ES+): 282.2 (M+1, 100%).

19. 5-(4-fluoro-3-methylphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 4-fluoro-3-methylbenzoyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 23 mg(2%) of the compound. MS (m/z, ES+): 296.3 (M+1, 100%).

20. 5-(4-fluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 4-fluorobenzoyl chloride. The crude material was purifiedby column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 27 mg (3%) of thecompound. MS (m/z, ES+): 282.3 (M+1, 100%).

21. 5-(2,5-dimethoxybenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from (2,5-dimethoxyphenyl)acetyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 34 mg(3%) of the compound. MS (m/z, ES+): 338.4 (M+1, 100%).

22. 5-(1-ethylpropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 2-ethylbutyryl chloride. The crude material was purifiedby column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 32 mg (3%) of thecompound. MS (m/z, ES+): 258.5 (M+1, 100%).

23. 5-isobutyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine was preparedfrom 3-methylbutyryl chloride. The crude material was purified by columnchromatography (CH₂Cl₂:CH₃OH=20:1) to yield 66 mg (7%) of the compound.MS (m/z, ES+): 244.4 (M+1, 100%).

24. 5-(3,4-difluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3,4-difluorobenzoyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 18 mg(2%) of the compound. MS (m/z, ES+): 300.3 (M+1, 100%).

25.2′,5′-dimethyl-4-(phenylhydrazono)-4H,2′H-[3,3′]bipyrazolyl-5-ylaminewas prepared from 2,5-dimethyl-2H-pyrazole-3-carbonyl chloride. Thecrude material was purified by column chromatography (CH₂Cl₂:CH₃OH=20:1)to yield 17 mg (2%) of the compound. MS (m/z, ES+): 282.3 (M+1, 100%).

26. 5-(4-methyl-3-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 4-methyl-3-nitrobenzoyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 38 mg(3%) of the compound. MS (m/z, ES+): 323.2 (M+1, 100%).

27. 4-(phenylhydrazono)-5-quinoxalin-2-yl-4H-pyrazol-3-ylamine wasprepared from quinoxaline-2-carbonyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 7 mg (1%)of the compound. MS (m/z, ES+): 316.2 (M+1, 100%).

28.5-(2-methylsulfanylpyridin-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 2-methylsulfanyinicotinoyl chloride. The crudematerial was purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) toyield 14 mg (1%) of the compound. MS (m/z, ES+): 311.4 (M+1, 100%),264.2 (M-46, 60%).

29.5-(4-methyl-[1,2,3]thiadiazol-5-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 4-methyl-[1,2,3]thiadiazole-5-carbonyl chloride. Thecrude material was purified by column chromatography (CH₂Cl₂:CH₃OH=20:1)to yield 9 mg (1%) of the compound. MS (m/z, ES+): 286.2 (M+1, 100%).

30. 4-(phenylhydrazono)-5-(3,4,5-trimethoxyphenyl)-4H-pyrazol-3-ylaminewas prepared from 3,4,5-trimethoxybenzoyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 12 mg(1%) of the compound. MS (m/z, ES+): 354.3 (M+1, 100%).

31.4-(phenylhydrazono)-5-(4-trifluoromethylsulfanylphenyl)-4H-pyrazol-3-ylaminewas prepared from 4-trifluoromethylsulfanylbenzoyl chloride. The crudematerial was purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) toyield 29 mg (2%) of the compound. MS (m/z, ES+): 364.3 (M+1, 100%).

32. 5-(3,5-difluorophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3,5-difluorobenzoyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 36 mg(3%) of the compound. MS (m/z, ES+): 300.4 (M+1, 100%).

33. 5-(6-chloropyridin-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 6-chloronicotinoyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 23 mg(2%) of the compound. MS (m/z, ES+): 299.4 (Cl³⁵M+1, 100%), 301.0(Cl³⁷M+1, 70%).

34. 5-(3-phenoxypropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 4-phenoxybutyryl chloride. The crude material was purifiedby column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 38 mg (3%) of thecompound. MS (m/z, ES+): 322.3 (M+1, 100%).

35. 5-(2,2-dimethylpropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3,3-dimethylbutyryl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 4 mg(0.5%) of the compound. MS (m/z, ES+): 258.2 (M+1, 100%).

36. 5-(2-phenylcyclopropyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from trans-2-phenylcyclopropanecarbonyl chloride. The crudematerial was purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) toyield 8 mg (0.5%) of the compound. MS (Mm/z): 304.6 (M+1, 100%).

37. 5-(2-methylsulfanylethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 3-methylsulfanylpropionyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 35 mg(3%) of the compound. MS (m/z, ES+): 262.2 (M+1, 100%).

38. 5-(3,4-dimethoxybenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from (3,4-dimethoxyphenyl)acetyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 19 mg(1%) of the compound. MS (m/z, ES+): 338.4 (M+1, 100%).

39. 5-benzo[b]thiophen-2-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from benzo[b]thiophene-2-carbonyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 14 mg(1%) of the compound. MS (m/z, ES+): 320.2 (M+1, 100%).

40. 5-(3-fluoro-4-methylphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 3-fluoro-4-methylbenzoyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 24 mg(2%) of the compound. MS (m/z, ES+): 296.3 (M+1, 100%).

41. 5-(2-nitrophenoxymethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from (2-nitrophenoxy)acetyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 20 mg(1%) of the compound. MS (m/z, ES+): 339.3 (M+1, 80%), 200.2 (M−138,100%).

42.5-(5-methyl-3-phenylisoxazol-4-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 5-methyl-3-phenylisoxazole-4-carbonyl chloride. Thecrude material was purified by column chromatography (CH₂Cl₂:CH₃OH=20:1)to yield 16 mg (1%) of the compound. MS (m/z, ES+): 345.2 (M+1, 100%).

43.4-(phenylhydrazono)-5-(2-trifluoromethoxyphenyl)-4H-pyrazol-3-ylaminewas prepared from 2-trifluoromethoxybenzoyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 41 mg(3%) of the compound. MS (m/z, ES+): 348.3 (M+1, 90%), 349.3 (M+2,100%).

44. 4-(phenylhydrazono)-5-(4-trifluoromethylphenyl)-4H-pyrazol-3-ylaminewas prepared from 4-trifluoromethylbenzoyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 23 mg(2%) of the compound. MS (m/z, ES+): 332.4 (M+1, 100%).

45. 5-(3,4-dimethylphenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3,4-dimethylbenzoyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 23 mg(2%) of the compound. MS (m/z, ES+): 292.3 (M+1, 100%), 293.4 (M+2,100%).

46. 5-phenethyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine was preparedfrom 3-phenylpropionyl chloride. The crude material was purified bycolumn chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 23 mg (2%) of thecompound. MS (m/z, ES+): 292.2 (M+1, 100%).

47. 1′-phenyl-4-(phenylhydrazono)-5′-propyl-4H,1′H-[3,4′]bipyrazolyl-5-ylamine was prepared from1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride. The crude materialwas purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 28 mg(2%) of the compound. MS (m/z, ES+): 372.3 (M+1, 100%).

48. 5-isopropyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine was preparedfrom isobutyryl chloride. The crude material was purified by columnchromatography (CH₂Cl₂:CH₃OH=20:1) to yield 22 mg (2%) of the compound.MS (m/z, ES+): 230.3 (M+1, 100%).

49. N-{4-[5-amino-4-(phenylhydrazono)-4H-pyrazol-3-yl]phenyl}acetamidewas prepared from 4-acetylaminobenzoyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 66 mg(5%) of the compound. MS (m/z, ES+): 321.4 (M+1, 100%), 322.4 (M+2,100%).

50. 5-(3-chlorothiophen-2-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 3-chlorothiophene-2-carbonyl chloride. The crudematerial was purified by column chromatography (CH₂Cl₂:CH₃OH=20:1) toyield 48 mg (4%) of the compound. MS (m/z, ES+): 304.2 (Cl³⁵M+1, 100%),306.4 (Cl³⁷M+1, 90%).

51. 5-(3-Methoxybenzyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from (3-methoxyphenyl)acetyl chloride. The crude material waspurified by column chromatography (CH₂Cl₂:CH₃OH=20:1) to yield 15 mg(1%) of the compound. MS (m/z, ES+): 308.3 (M+1, 100%).

52. 5-(2,5-dimethylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 3-(2,5-dimethylfuran-3-yl)-3-oxopropionitrile (0.6mmol). The product was purified by precipitation from isopropanol by theaddition of water to yield 26 mg (42%) of the compound. ¹H NMR (ppm, 500MHz, CDCl₃) δ 7.30 (d, 1H), 7.45 (t, 1H), 7.34 (t, 1H), 6.29 (s, 1H),5.65 (br s, 2H), 2.50 (s, 3H), 2.33 (s, 3H); MS (m/z, ES+): 282.3 (M+1,100%).

53.5-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-2H-[1,2,3]triazole-4-carboxylicacid was prepared from3-[3-(4-chlorophenylsulfanylmethyl)phenyl]-3-oxopropionamide (0.05mmol). The crude material was purified by column chromatography(CH₂Cl₂:CH₃OH=20:1) to yield 13 mg of the compound. MS (m/z, ES+): 420.3(Cl³⁵M+1, 100%), 422.3 (Cl³⁷M+1, 80%).

54. 4-(phenylhydrazono)-5-thiophen-3-yl-4H-pyrazol-3-ylamine wasprepared from 3-oxo-3-thiophen-3-yl-propionitrile (1.0 mmol). The crudematerial was purified by recrystallization to yield 33 mg (12%) of thecompound. MS (m/z, ES+): 270.3 (M+1, 100%).

55. 5-(2-nitrophenyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3-(2-nitro-phenyl)-3-oxopropionitrile (1.0 mmol). Thecrude material was purified by recrystallization to yield 17 mg (6%) ofthe compound. MS (m/z, ES+): 309.3 (M+1, 100%).

56.5-(1-methyl-1-[1,2,4]triazol-1-ylethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 4-methyl-3-oxo-4-[1,2,4]triazol-1-ylpentanenitrile(1.0 mmol). The crude material was purified by recrystallization toyield 29 mg (10%) of the compound. MS (m/z, ES+): 297.4 (M+1, 80%),228.3 (M−68, 100%).

57.5-(5-methyl-2-trifluoromethylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from3-(5-methyl-2-trifluoromethylfuran-3-yl)-3-oxopropionitrile (1.0 mmol).The crude material was purified by column chromatography to yield 14 mg(4%) of the compound. MS (m/z, ES+): 336.3 (M+1, 100%).

58.5-(2-tert-butyl-5-methylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 3-(2-tert-butyl-5-methylfuran-3-yl)-3-oxopropionitrile(1.0 mmol). The crude material was purified by column chromatography toyield 30 mg (10%) of the compound. MS (m/z, ES+): 324.4 (M+1, 100%).

59. 5-(2-methylfuran-3-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3-(2-methylfuran-3-yl)-3-oxopropionitrile (1.0 mmol). Thecrude material was purified by column chromatography and was thenrecrystallized to yield 28 mg (10%) of the compound. MS (m/z, ES+):268.3 (M+1, 100%).

60. 5-furan-2-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine was preparedfrom 3-furan-2-yl-3-oxopropionitrile (1.0 mmol). The crude material waspurified by recrystallization to yield 71 mg (28%) of the compound. MS(m/z, ES+): 254.3 (M+1, 100%).

61. 4-(phenylhydrazono)-5-quinolin-6-yl-4H-pyrazol-3-ylamine wasprepared from 3-oxo-3-quinolin-6-ylpropionitrile (0.5 mmol). The productwas isolated without further purification to yield 11 mg (7%) of thecompound. MS (m/z, ES+): 315.2 (M+1, 100%).

62.5-[5-(4-chlorophenyl)-2-methylfuran-3-yl]-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from3-[5-(4-chlorophenyl)-2-methylfuran-3-yl]-3-oxopropionitrile (0.2 mmol).The product was isolated without further purification to yield 15 mg(21%) of the compound. MS (m/z, ES+): 378.4 (Cl³⁵M+1, 100%), 380.4(Cl³⁷M+1, 50%).

63. 5-benzo[b]thiophen-3-yl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 3-benzo[b]thiophen-3-yl-3-oxopropionitrile (0.5 mmol). Theproduct was isolated without further purification to yield 17 mg (11%)of the compound. MS (m/z, ES+): 320.2 (M+1, 100%).

64.5-(4-Chlorophenyl-sulfanylmethyl)-4-(phenylhydrazono)-4H-pyrazol-3-ylaminewas prepared from 4-(4-chlorophenylsulfanyl)-3-oxobutyronitrile (0.5mmol) The crude material was purified by column chromatography(CH₂Cl₂:CH₃OH=20:1) to yield 13 mg of the compound. MS (m/z, ES+): 420.3(Cl³⁵M+1, 100%), 422.3 (Cl³⁷M+1, 80%).

Example 70 Preparation of5-cyclopropyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine

A. Ethyl cyclopropylcarboxylate (5.6 g, 49.1 mmol) and acetonitrile (7mL) were premixed and added into a suspension of potassium tert-butoxide(15 g, 133.7 mmol) in 250 mL of dry toluene at 70° C. This mixture wasstirred at 80° C. overnight. The solid precipitate was collected byfiltration, washed with ethyl acetate and diethyl ether, and dried invacuo. The product was isolated as its potassium salt (6.78 g).

B. To an ice cold suspension of 3-aminopyridine (0.56 g, 5.95 mmole) in9.2 mL of water was added conc. HCl (1.46 mL, 18 mmol). NaNO₂ (0.54 g,8.51 mmole) dissolved in 2.5 mL of water was added to this mixtureslowly. Half of this diazonium solution was then added to the mixture ofthe potassium salt of 3-cyclopropyl-3-oxopropionitrile (0.6 g, 5.49mmole) obtained above and NaOAc trihydrate (2 g, 14.7 mmole) dissolvedin 15 mL of water at 10° C. The precipitate was collected by filtrationand then resuspended in 30 mL of ethanol. Hydrazine hydrate (0.5 mL) wasadded slowly to this suspension at 80° C. and the mixture was stirred atthis temperature for 2 hours. The solvents were removed in vacuo. Thetitle compound was obtained after recrystallization from ethanol in ayield of 0.28 g. MS (m/z, ES+): 229 (M+1, 100%).

C. In a similar manner,3-[N′-(3-amino-5-cyclopropylpyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamidewas prepared from 3-amino-N-methylbenzenesulfonamide (0.385 g, 2.06mmol) to yield 0.21 g of the product. MS (m/z, ES+): 321 (M+1, 100%).

D. In a similar manner,3-[N′-(3-amino-5-cyclopropylpyrazol-4-ylidene)hydrazino]-N-(2-hydroxyethyl)benzenesulfonamidewas prepared from 3-amino-N-(2-hydroxyethyl)benzenesulfonamide (0.55 g,2.54 mmol) to yield 0.3 g of the product. MS (m/z, ES+): 351 (M+1,100%).

E. In a similar manner,3-[N′-(3-amino-5-cyclopropylpyrazol-4-ylidene)hydrazino]benzenesulfonamidewas prepared from 3-aminobenzenesulfonamide (0.51 g, 2.96 mmol) to yield0.1 g of the product. MS (m/z, ES+): 307 (M+1, 100%).

Example 71

The compounds in this example were prepared by the following procedure:Concentrated hydrochloric acid (1.46 mL, 17.5 mmol) was added drop-wiseto a solution of the substituted aniline (6.0 mmol) dissolved in 9.2 mLof water at 0° C. To this mixture was then added a cooled solution ofNaNO₂ (0.54 g, 7.8 mmol) dissolved in 4 mL of water. The solution wasstirred for 30 minutes and was then added to a solution of thesubstituted pyrazole (6.2 mmol) and NaOAc trihydrate (3.3 g, 24 mmol)dissolved in a mixture of water (6 mL) and AcOH (6 mL). The resultingsolid was isolated by filtration and dried. The crude material waspurified by recrystallization or column chromatography.

1. 5-methyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine was prepared fromaniline (0.56 g, 6.0 mmol) and 3-amino-5-methylpyrazole (0.6 g, 6.2mmol). The resulting solid was isolated by filtration and dried. Thecrude material was purified by recrystallization from ethylacetate/hexanes to yield 0.21 g (18%) of the compound as a yellow solid.¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 11.8 (br s, 1H), 7.65 (m, 2H), 7.4 (m,2H), 7.3 (m, 1H), 6.6 (br s, 2H), 2.2 (s, 3H); MS (m/z, ES+): 202.1(M+1, 100%).

2. 4-(3-fluorophenylhydrazono)-5-methyl-2H-pyrazol-3-ylamine wasprepared from 3-fluoroaniline (0.66 g, 6.0 mmol) and3-amino-5-methylpyrazole (0.54 g, 5.6 mmol). The crude material waspurified by column chromatography eluting with CH₂Cl₂:CH₃OH (9:1) toyield 0.227 g (19%) of the compound as an orange solid.

3. 4-[(3-chlorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-ylamine wasprepared from 3-chloroaniline (0.77 g, 6.0 mmol) and3-amino-5-methylpyrazole (0.58 g, 6.0 mmol). The crude material waspurified by chromatography (CH₂Cl₂:CH₃OH=10:1) to yield 0.41 g (22%) ofthe compound as an orange solid.

4. 5-methyl-4-[(4H-[1,2,4]triazol-3-yl)hydrazono]-4H-pyrazol-3-ylaminewas prepared from 3-amino-1,2,4-triazole (0.88 g, 10.5 mmol) and3-amino-5-methylpyrazole (1.0 g, 10.3 mmol). The crude material wasextracted from the aqueous layer three times with ethyl acetate (100mL). The combined ethyl acetate solutions were washed with brine, driedover magnesium sulphate, filtered and evaporated. A portion of the crudematerial was purified by column chromatography (CHCl₃:CH₃OH=7:1). Theisolated material was then further purified by preparative TLC(CHCl₃I:CH₃OH=7:1) to yield 0.047 g (8%) of the compound as a red solid.¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 12.0 (br s, 1H), 8.2 (br s, 1H), 6.8(br s, 2H), 2.2 (s, 3H).

5.3-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-1H-pyrazole-4-carboxylicacid ethyl ester was prepared from 3-amino-4-carbethoxypyrazole (0.46 g,3.0 mmol) and 3-amino-5-methylpyrazole (0.50 g, 5.1 mmol). The water wasremoved by evaporation and the crude material was purified byrecrystallization from ethanol to yield 0.43 g (58%) of the compound asan orange solid.

6.3-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-1H-pyrazole-4-carboxylicacid was prepared by dissolving3-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-1H-pyrazole-4-carboxylicacid ethyl ester (0.2 g, 0.8 mmol) in ethanol containing sodiumhydroxide (0.2 g, 5 mmol) and the solution was stirred overnight. Themixture was then acidified to pH 1 with 1N hydrochloric acid and theresulting solid was isolated by filtration. The crude material waspurified by preparative TLC eluting with (CHCl₃:MeOH:H₂O=4:1:0.005) toyield 39 mg (22%) of the compound as a red solid.

7. 4-[(3,4-difluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-ylamine wasprepared from 3,4-difluoroaniline (0.62 g, 4.8 mmol) and3-amino-5-methylpyrazole (0.6 g, 6.2 mmol) according to proceduredescribed above except that the substituted aniline was initiallydissolved in a mixture of water (7.2 mL) and DMF (2.0 mL) prior to beingacidified. The crude material was initially purified by columnchromatography (CH₂Cl₂:MeOH=20:1). The isolated material was furtherpurified by recrystallization from ethyl acetate/hexanes to yield 0.2 g(18%) of the compound as a yellow solid. MS (m/z, ES+): 238.1 (M+1,100%).

8. 5-methyl-4-[(4-trifluoromethylphenyl)hydrazono]-4H-pyrazol-3-ylaminewas prepared from 4-trifluoromethylaniline (0.36 g, 2.2 mmol) and3-amino-5-methylpyrazole (0.3 g, 3.1 mmol) according to proceduredescribed above except that the substituted aniline was initiallydissolved in a mixture of water (3.6 mL) and DMF (2.0 mL) prior to beingacidified. The crude material was purified by column chromatography(CHCl₃:MeOH=10:1) to yield 0.041 g (7%) of the compound as an orangesolid. MS (m/z, ES+): 270.2 (M+1, 100%).

9. 5-methyl-4-[(3-nitrophenyl)hydrazono]-4H-pyrazol-3-ylamine wasprepared from 3-nitroaniline (0.35 g, 2.5 mmol) and3-amino-5-methylpyrazole (0.3 g, 3.1 mmol) according to the proceduredescribed above except that the substituted aniline was initiallydissolved in a mixture of water (3.6 mL) and DMF (2.0 mL) prior to beingacidified. The product was isolated in a yield of 176 mg (29%) of thecompound as a red solid and was not further purified. MS (m/z, ES+):247.2 (M+1, 100%).

10. 4-(isoquinolin-5-ylhydrazono)-5-methyl-4H-pyrazol-3-ylamine wasprepared from 5-aminoisoquinoline (0.7 g, 4.9 mmol) and3-amino-5-methylpyrazole (0.6 g, 6.2 mmol) according to the proceduredescribed above except that the substituted aniline was initiallydissolved in a mixture of water (6.0 mL) and DMF (6.0 mL) prior to beingacidified. The crude material was purified by chromatography elutingwith (CH₂Cl₂:MeOH=6:1) to yield 0.089 g (7%) of the compound as a redsolid. MS (m/z, ES+): 253.2 (M+1, 50%), 129 (M−123, 100%).

11. 5-methyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine was preparedfrom 3-aminopyridine (0.6 g, 6.3 mmol) and 3-amino-5-methylpyrazole (0.6g, 6.2 mmol). The crude material was purified by recrystallization fromethanol to yield 0.35 g (27%) of the compound as a yellow/orange solid.

12. 5-methyl-4-(phthalazin-5-ylhydrazono)-4H-pyrazol-3-ylamine wasprepared from 5-aminophthalazine (0.25 g, 1.7 mmol) and3-amino-5-methylpyrazole (0.5 g, 5.2 mmol). The crude material waspurified by column chromatography eluting with dichloromethane/methanol(4:1) to yield 0.031 g (7%) of the compound as a red solid. MS (m/z,ES+): 254 (M+1, 100%).

13. 4-[(4-methoxyphenyl)hydrazono]-5-methyl-4H-pyrazol-3-ylamine wasprepared from anisole (0.25 g, 2 mmol) and 3-amino-5-methylpyrazole (0.2g, 2 mmol) according to the procedure described above except that the3-amino-5-methylpyrazole was dissolved in 2 mL of water containing NaOActrihydrate (1.1 g, 8 mmol). The resulting crude material was purified byflash silica gel chromatography eluting with (CH₂Cl₂:EtOH=10:2) to yield0.054 g (12%) of the compound as a yellow solid. ¹H NMR (ppm, 500 MHz,DMSO-d₆) δ 7.67 (d, 2H), 7.01 (d, 2H), 3.8 (s, 3H), 2.4 (s, 3H); MS(m/z, ES−): 230.2 (M−1, 100%).

14. 4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine was prepared from3-fluoroaniline (0.33 g, 3.0 mmol) and 3-aminopyrazole (0.25 g, 3.0mmol). The crude material was extracted from the aqueous layer threetimes with ethyl acetate (15 mL). The combined ethyl acetate solutionswere washed with brine, dried over magnesium sulphate, filtered andevaporated. The crude material was purified by flash silica gelchromatography eluting with (CHCl₃:MeOH=9:1) to yield 0.063 g (10%) ofthe compound as a yellow solid. ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 12.0(br s, 1H), 7.8 (br s, 1H), 7.4-7.8 (m, 4H), 6.8-7.2 (m, 3H).

15. 4-(phenylhydrazono)-4H-pyrazol-3-ylamine was prepared from aniline(0.56 g, 6.0 mmol) and 3-aminopyrazole (0.51 g, 6.1 mmol). The water wasremoved under reduced pressure and the resulting crude material waspurified by column chromatography (CHCl₃:MeOH=9:1) to yield 0.071 g (6%)of the compound as a yellow solid. ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 12.0(br s, 1H), 7.8 (br s, 1H), 7.6-7.8 (m, 2H), 7.2-7.6 (m, 3H), 6.8 (br s,1H), 6.2 (br s, 1H).

16. 4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine was preparedfrom 3,4-difluoroaniline (0.62 g, 4.8 mmol) and 3-aminopyrazole (0.4 g,4.8 mmol) according to the procedure described above except that theaniline was initially dissolved in a mixture of water (7.2 mL) and DMF(1.16 mL) prior to being acidified. The solvents were removed underreduced pressure and the resulting crude material was purified by columnchromatography eluting with (CHCl₃:MeOH=10:1) to yield 0.41 g (38%) ofthe compound as a yellow solid. ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 12.0(br s, 1H), 7.2-8.0 (m, 4H), 6.9 (m, 2H).

17. 4-[N′-(3-aminopyrazol-4-ylidene)hydrazino]benzenesulfonamide wasprepared from 4-aminobenzenesulfonamide (1.0 g, 5.8 mmol) and3-aminopyrazole (0.8 g, 9.6 mmol) according to the procedure describedabove except that the 3-aminopyrazole was dissolved in 30 mL of watercontaining NaOAc trihydrate (5.5 g, 40 mmol). The resulting crudematerial was purified by column chromatography (CH₂Cl₂:MeOH=10:1) toyield 0.121 g (8%) of the compound as a yellow solid. MS (m/z, ES+):267.0 (M+1, 100%).

18. 4-[(3-fluoro-4-methoxyphenyl)hydrazono]-4H-pyrazol-3-ylamine wasprepared from 3-fluoro-p-anisidine (0.47 g, 3.3 mmol) and3-aminopyrazole (0.6 g, 7.2 mmol) according to the procedure describedabove except that the 3-aminopyrazole was dissolved in 30 mL of watercontaining NaOAc trihydrate (5.5 g, 40 mmol). The resulting crudematerial was recrystallized from ethyl acetate/hexanes and the furtherpurified by column chromatography (CH₂Cl₂:MeOH=5:1) to yield 0.081 g(10%) of the compound as a yellow solid. MS (m/z, ES+): 236.1 (M+1,100%).

19. 5-tert-butyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine wasprepared from 3-fluoroaniline (0.33 g, 3.0 mmol) and3-amino-5-tert-butylpyrazole (0.4 g, 3.0 mmol). The solvent was removedunder reduced pressure and the resulting crude material was purified bycolumn chromatography (CH₂Cl₂:MeOH=9:1) to yield 0.099 g (13%) of thetitle compound as an orange solid. ¹H NMR (ppm, 200 MHz, DMSO-d₆) δ 11.6(br s, 1H), 7.4-7.7 (m, 4H), 7.1 (br s, 2H), 1.4 (s, 9H).

Example 72

A. The compounds described in this example were prepared according tothe following procedure: Concentrated HCl (1.46 mL, 17.5 mmol) was addeddrop wise to a solution of the substituted aniline (6.0 mmol) dissolvedin 9.2 mL of water at 0° C. To this mixture was then added a cooledsolution of NaNO₂ (0.54 g, 7.8 mmol) in 4 mL of water. The solution wasstirred for 30 minutes and was then added to a solution of thesubstituted pyrazole (6.2 mmol) and NaOAc trihydrate (3.3 g, 24 mmol)dissolved in a mixture of water (6 mL) and AcOH (6 mL). The resultingsolid was isolated by filtration and dried. The crude material waspurified by recrystallization or column chromatography.

1. {4-[(3,4-Difluorophenyl)hydrazono]-4H-pyrazol-3-yl}ethylamine wasprepared from 3,4-difluoroaniline (0.31 g, 2.4 mmol) andethyl-(1H-pyrazol-3-yl)amine (0.27 g, 2.4 mmol) according to theprocedure described above except that the substituted aniline wasdissolved in water (3 mL) and DMF (1 mL). The resulting solid waspurified by preparative TLC (EtOAc:hexane=1:1) to yield 0.047 g (8%) ofthe compound as an orange solid. MS (m/z, ES+): 252.1 (M+1, 100%).

2.Ethyl-{4-[(3-methyl-3H-benzotriazol-5-yl)hydrazono]-4H-pyrazol-3-yl}aminewas prepared from 3-methyl-5-aminobenzotriazole (0.25 g, 1.7 mmol) andethyl-(1H-pyrazol-3-yl)amine (0.18 g, 1.6 mmol). The resulting solid waspurified by preparative TLC (EtOAc:hexane=1:1) to yield 0.063 g (12%) ofthe compound as a yellow solid. MS (m/z, ES+): 271.2 (M+1, 100%).

3. 4-[N′-(3-Ethylaminopyrazol-4-ylidene)-hydrazino]benzenesulfonamidewas prepared from 4-aminobenzenesulfonamide (0.41 g, 2.4 mmol) andethyl-(1H-pyrazol-3-yl)-amine (0.27 g, 2.4 mmol). The crude material waspurified by preparative TLC (CHCl₃:MeOH=6:1) to yield 0.081 g (12%) ofthe title compound as a yellow solid. MS (m/z, ES+): 295.1 (M+1, 65%).

4. Ethyl-[4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-yl]amine was preparedfrom 3-aminopyridine (0.41 g, 4.4 mmol) andethyl-(1H-pyrazol-3-yl)-amine (0.27 g, 2.4 mmol). The crude material waspurified by preparative TLC (CH₂Cl₂:MeOH=9:1) to yield 0.081 g (12%) ofthe compound as an orange solid. MS (m/z, ES+): 217.2 (M+1, 100%).

5. Ethyl-[4-(isoquinolin-5-ylhydrazono)-4H-pyrazol-3-yl]amine wasprepared from 5-aminoisoquinoline (0.5 g, 3.5 mmol) andethyl-(1H-pyrazol-3-yl)amine (0.3 g, 2.7 mmol). The crude material waspurified by preparative TLC (CHCl₃:MeOH=5:1) to yield 0.039 g (4%) ofthe compound as an orange solid.

B. A solution of 3-aminopyrazole (1.0 g, 12.0 mmol) in 10 mL of formicacid was heated to 108° C. for 12 hours in a round bottom flask equippedwith a condenser and a magnetic stirring bar. The formic acid was thenremoved by vacuum distillation and the white product was washed withwater. The resulting solid was then dried under high vacuum overnight toyield 1.34 g (96%) of N-(2H-pyrazol-3-yl)formamide. To this solid (0.31g, 2.8 mmol) in 10 mL of anhydrous THF at −10° C. was added excesslithium aluminum hydride. The reaction was stirred under argon overnightand then quenched with a saturated sodium bicarbonate solution. Theresulting white solid was removed by filtration and the mother liquorwas then dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure. Methyl-(2H-pyrazol-3-yl)amine was isolated in a yieldof 0.317 g (120%) as a pale brown oil and was used in subsequentreactions without further purification.

1. {4-[(3,4-Difluorophenyl)hydrazono]-4H-pyrazol-3-yl}methylamine wasprepared from 3,4-difluoroaniline (0.44 g, 3.41 mmol) and3-(N-methylamino)pyrazole (0.30 g, 3.1 mmol) according to the proceduredescribed above in Paragraph A with the following exceptions. Thesubstituted aniline was dissolved in water (3 mL) and DMF (1 mL). Thesubstituted pyrazole and NaOAc trihydrate (1.9 g, 13.95 mmol) weredissolved in 5 mL of water. The resulting solid was purified bypreparative TLC (EtOAc:hexane=4:1) to yield 30 mg (3%) of the titlecompound as an orange solid. MS (m/z, ES+): 238 (M+1, 100%).

C. A solution of 3-amino-5-methylpyrazole (2.3 g, 23.7 mmol) dissolvedin glacial acetic acid (15 mL) was refluxed at 120° C. for 16 hours toafford a transparent yellow solution. This solution was cooled toambient temperature which resulted in the formation of white needles.The crystals were isolated via filtration, washed with water until thepH of the water became neutral and dried under high vacuum to yield 0.73g (22%) of N-(5-methyl-2H-pyrazol-3-yl)acetamide. This solid (0.43 g,3.1 mmol) was then suspended in 10 mL of anhydrous THF at 0° C. underargon. Excess lithium aluminum hydride in anhydrous THF (10 mL) wasadded over 24 hours and was stirred for an additional 48 hours. Thereaction mixture was quenched by the careful addition of a saturatedsodium bicarbonate solution. The solids were washed with THF and theorganics were combined, dried over anhydrous MgSO₄ and evaporated toyield 0.29 g (81%) of ethyl-(5-methyl-2H-pyrazol-3-yl)amine as a yellowoil.

1.{4-[(3,4-difluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}ethylaminewas prepared from 3,4-difluoroaniline (0.33 g, 3.5 mmol) andethyl-(5-methyl-2H-pyrazol-3-yl)amine (0.29 g, 2.34 mmol) according tothe procedure described above in Paragraph A with the followingexceptions. The substituted aniline was initially dissolved in a mixtureof water (4 mL) and DMF (1 mL) prior to being acidified. The substitutedpyrazole was mixed with NaOAc trihydrate (0.73 g, 8.87 mmol) in 6 mL ofwater. The resulting yellow precipitate was isolated by filtration anddried under high vacuum to afford 600 mg of crude material. A portion ofthe solid (300 mg) was dissolved in 17 mL of ethyl acetate and extractedwith 80 mL (8×10 mL) of 1.56 N HCl. The aqueous phase was thenneutralized with a saturated sodium bicarbonate solution yielding ayellow precipitate which was isolated by filtration (170 mg). The solidwas purified by preparative TLC (CH₂Cl₂:MeOH=98:2) to yield 0.052 g(17%) of the compound as a yellow solid. ¹H NMR (ppm, 200 MHz, DMSO-d₆)δ□12.1 (br s□□1H), 7.3-7.8 (m, 3H), 3.3 (merged with H₂O), 2.5 (s, 1H),1.1 (t, 3H).

2. Ethyl-[5-methyl-4-(pyridin-3-yl-hydrazono)-4H-pyrazol-3-yl]amine wasprepared from 3-aminopyridine (0.31 g, 3.5 mmol) andethyl-(5-methyl-2H-pyrazol-3-yl)amine (0.5 g, 3.2 mmol) with theexception that the substituted pyrazole was mixed with NaOAc trihydrate(0.73 g, 5.48 mmol) in 6 mL of water. The resulting crude material waspurified by preparative TLC (CH₂Cl₂:MeOH=9:1) to yield 0.040 g (5%) ofthe compound as a yellow solid. MS (m/z, ES+): 231 (M+1, 100%).

3. Ethyl-{4-[(3-fluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}aminewas prepared from 3-fluoroaniline (0.33 g, 3.5 mmol) andethyl-(5-methyl-2H-pyrazol-3-yl)amine (0.5 g, 3.2 mmol) according toprocedure described in Paragraph A above with the exception that thesubstituted pyrazole was mixed with NaOAc trihydrate (0.73 g, 5.48 mmol)in 6 mL of water. The resulting crude material was purified bypreparative TLC eluting with (CH₂Cl₂:MeOH=9:1) to yield 0.036 g (4%) ofthe title compound as a yellow solid. MS (m/z, ES+): 248 (M+1, 100%).

D. A solution of 3-amino-5-methylpyrazole (5.33 g, 54.8 mmol) in 20 mLformic acid was heated to 108° C. in a round bottom flask equipped witha condenser and a magnetic stirring bar. The reaction was stirredovernight, at which point the formic acid was removed by vacuumdistillation. The product was then washed with water, which was alsoremoved by vacuum distillation. The white product,N-(5-methyl-2H-pyrazol-3-yl)-formamide, was then dried in vacuo. Thissolid was then partially dissolved in 50 mL of anhydrous THF underargon. The reaction solution was cooled to −10° C. and an excess oflithium aluminum hydride was added slowly while stirring. The solutionwas allowed to warm to room temperature over 24 hours. The reactionmixture was then cooled to −10° C. and was quenched by the addition of asaturated sodium bicarbonate solution. The resulting solution wasfiltered and the solids were washed with THF. The filtrate was driedover anhydrous MgSO₄, filtered, and concentrated to yield 6.8 g (100%)of methyl-(5-methyl-2H-pyrazol-3-yl)amine. ¹H NMR (ppm, 300 MHz,DMSO-d₆) δ□11.0 (br s□□1H), 5.17 (s, 1H), 4.80 (br s, 1H), 2.5 (d, 3H),2.1 (s, 3H).

1.{4-[(3,4-difluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}methylaminewas prepared from 3,4-difluoroaniline (750 mg, 7.92 mmol) and3-(N-methylamino)-5-methylpyrazole (0.80 g, 7.2 mmol) according to theprocedure described in Paragraph A above with the following exceptions.The substituted aniline was dissolved in a mixture of water (8 mL) andDMF (2 mL). The substituted pyrazole was mixed with NaOAc trihydrate(3.64 g, 27.3 mmol) in 10 mL of water. The resulting solid was purifiedby column chromatography (EtOAc:hexane=1:1) to yield 0.70 g (39%) of aby-product and 0.145 g (8%) of the compound as a yellow solid. MS (m/z,ES+): 252 (M+1, 100%); ¹H NMR (ppm, 400 MHz, DMSO-d₆) δ 2.3 (s, 3H), 2.5(s, 3H) {2.5/2.3=1.5}3.2 (d, 3H) 3.3 (d, 3H) {3.3/3.2=1.5}6.6 (bs, 1H),7.6-8.0 (m, 4H) 12.0 (bs, 1H) 12.3 (bs, 1H) {12.0/12.3=1.5}[*Ratiosindicate tautamers]; ¹H NMR (ppm, DMSO-d₆+D₂O, 400 MHz) δ 2.5 (s, 3H),3.2 (s, 3H), 7.1-7.6 (m, 3H); FTIR (cm⁻¹, KBr pellet) 490 (w), 516 (w),550 (w), 724 (m), 770 (m), 819 (m), 868 (m), 983 (m), 1016 (m), 1087(m), 1141 (m), 1192 (m), 1257 (m), 1301 (m), 1335 (m), 1384 (m), 1429(s), 1506 (s), 1541 (m), 1626 (m), 2769 (m), 2808 (m), 2924 (m), 3045(m).

2. {4-[(3-Fluorophenyl)hydrazono]-5-methyl-4H-pyrazol-3-yl}methylaminewas prepared from 3-fluoroaniline (0.34 g, 3.06 mmol) and3-(N-methylamino)-5-methylpyrazole (0.32 g, 2.85 mmol) according to theprocedure describee above in Paragraph A with the exception that thesubstituted pyrazole was mixed with sodium acetate trihydrate (0.43 g,3.14 mmol) in 5 mL of water. The crude material isolated in an amount of0.46 g. An amount of this (0.25 g) was purified by column chromatography(EtOAc:hexane=1:1) to yield 0.050 g (13%) of the compound as a yellowsolid. MS (m/z, ES+): 234 (M+1, 100%).

E. Methyl isonicotinate (9 g, 60 mmol) and of acetonitrile (4 mL) werepremixed and added to a suspension of potassium tert-butoxide (10.6 g,94.5 mmol) in 200 mL of dry toluene at 80° C. This mixture was stirredat this temperature overnight. The solid precipitate was collected byfiltration and dried in vacuo. The product was isolated as the potassiumsalt in a yield of 10 g (92%). This salt (9 g, 49 mmol) was mixed withhydrazine hydrate (5 mL, 100 mmol) and concentrated HCl (4.5 mL, 54mmol) in ethanol (150 mL). The solution was refluxed for 8 hours atwhich point an additional 4 mL of hydrazine hydrate was added. Refluxingwas continued overnight. The solvent was removed by distillation and theresulting crude material was purified by column chromatography, elutingwith CH₂Cl₂:CH₃OH (5:1) to yield 4.1 g (52%) of5-pyridin-4-yl-2H-pyrazol-3-ylamine. This material (4.1 g, 26 mmol) wasdissolved in formic acid (50 mL) and heated to 70° C. for 2 hours. Theformic acid was removed by distillation to afford 4.5 g (92%) of(N-(5-pyridin-4-yl-2H-pyrazol-3-yl)formamide. The solid was dissolved inanhydrous THF (200 mL). Lithium aluminum hydride (3 g, 79 mmol)suspended in 200 mL of THF was added slowly and, once the addition wascomplete, the reaction was heated to reflux for 2 hours. The reactionwas quenched by the addition of saturated sodium sulphate solution andthe solution was passed through a celite cake. The residue was washedwith THF and methanol and the combined organic solutions wereconcentrated under reduced pressure. The resulting crude material waspurified by column chromatography (CH₂Cl₂:MeOH=5:1) to yield 1.8 g (43%)of methyl-(5-pyridin-4-yl-2H-pyrazol-3-yl)amine.

1.{4-[(3-fluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-yl}methylaminewas prepared from 3-fluoroaniline (70 mg, 0.69 mmol) andmethyl-(5-pyridin-4-yl-2H-pyrazol-3-yl)amine (0.1 g, 0.57 mmol)according to the procedure described in Paragraph A above with theexception that the substituted pyrazole was mixed with NaOAc trihydrate(0.31 g, 2.28 mmol) in water (2 mL) and DMF (1 mL). The resulting solidwas purified by column chromatography (EtOAc:hexane=4:1) to yield 0.15 g(88%) of the compound as a yellow solide. ¹H NMR (ppm, 400 MHz, DMSO-d₆)δ 13.0 (br s, 1H), 8.6 (dd, 2H), 8.2 (br s, 1H), 8.1 (dd, 2H), 7.45-7.7(m, 3H), 7.15 (dt, 1H), 3.0 (d, 3H); MS (m/z, ES+): 297 (M+1, 100%).

2.Mmethyl-[4-(phthalazin-5-ylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-yl]aminewas prepared from 4-aminoquinazoline (0.15 g, 1.04 mmol) andmethyl-(5-pyridin-4-yl-2H-pyrazol-3-yl)amine (0.2 g, 1.15 mmol)according to the procedure described above in Paragraph A with thefollowing exceptions. The substituted aniline was dissolved in water (5mL) and DMF (2 mL) prior to acidification. The substituted pyrazole wasmixed with NaOAc trihydrate (0.62 g, 4.59 mmol) in water (5 mL) and DMF(1 mL). The resulting solid was purified by column chromatography(EtOAc:hexane=4:1) to yield 0.080 g (23%) of the compound as an orangesolid. MS (m/z, ES+): 331 (M+1, 100%).

3.{4-[(3,4-difluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-yl}methylaminewas prepared from 3,4-difluoroaniline (75 mg, 0.57 mmol) andmethyl-(5-pyridin-4-yl-2H-pyrazol-3-yl)amine (0.1 g, 0.57 mmol)according to the procedure described above in Paragraph A with thefollowing exceptions. The substituted aniline was dissolved in water (1mL) and DMF (0.5 mL). The substituted pyrazole was mixed with NaOActrihydrate (0.32 g, 2.32 mmol) in water (3 mL) and DMF (1 mL). Theresulting solid was purified by column chromatography (EtOAc:hexane=4:1)to yield 0.02 g (11%) of the compound as an orange solid. MS (m/z, ES+):315 (M+1, 100%).

Example 73 Preparation oftert-butyl-[5-methyl-4-(phenylhydrazono)-4H-pyrazol-3-yl]amine

The title compound was prepared using 100 mg (0.4 mmol) ofN-tert-butyl-3-oxo-2-(phenylhydrazono)butyramide which was synthesizedusing aniline (1.7 mmol) and N-tert-butyl acetoacetamide (393 mg, 2.5mmol). Hydrazine hydrate (2.3 mmol) was added to a solution ofN-tert-butyl-3-oxo-2-(phenylhydrazono)butyramide in ethanol. Very littlesolid had formed after heating the reaction at 75° C. for 1 hour,however, analysis of the reaction solution by TLC indicated that nostarting material remained. The solution was allowed to cool to ambienttemperature and the solvent was evaporated. The residue wasrecrystallized from ethanol/water. The resulting solid was isolated byfiltration and dried to yield 38 mg (43%) of the title compound as ayellow solid. ¹H NMR (ppm, 200 MHz, CDCl₃) δ 1.42 (s, 9H), 2.20 (s, 3H),5.35 (br s, 1H), 6.95 (t, 1H), 7.15-7.35 (m, 4H), 9.95 (br s, 1H); IR(cm⁻¹, KBr pellet): 3368 (w), 3197 (w), 3038 (w), 2973 (w), 2928 (w),1631 (m), 1602 (m), 1565 (m), 1516 (s), 1498 (s), 1391 (w), 1366 (m),1225 (m), 1187 (w), 1166 (w), 1119 (w), 1074 (w), 1059 (w), 949 (w), 895(w), 775 (w), 748 (w), 691 (m), 561 (w); MS (m/z, ES+): 276.2 (M+18,5%), 259.2 (M+1, 1%), 203.1 (M-55, 5%).

Example 74 Preparation of(2-morpholin-4-ylethyl)[5-phenyl-4-(phenylhydrazono)-4H-pyrazol-3-yl]amine

5-Phenyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine (65 mg, 0.25 mmol) wasdissolved in 5 mL of acetonitrile. Potassium carbonate (70 mg, 0.5 mmol)and a catalytic amount of sodium iodide were added and the solution washeated to reflux. 4-(2-chloroethyl)morpholine hyrdochloride (50 mg, 0.25mmol) was added in small portions over 30 min. After heating at refluxfor 6 hours, the reaction was allowed to cool to ambient temperature andwas stirred overnight. Some of the residual 4-(2-chloroethyl)morpholinewas removed by stirring the solution over 50 mg of polystyrene boundthiophenol with 1 drop of diethylisopropylamine. The solution wasfiltered through celite and evaporated to a tan solid. The solid wasthen dissolved in ethyl acetate and precipitated with hexanes. The solidwas isolated by filtration and air dried. The material was purified bycolumn chromatography (CH₂Cl₂:MeOH=10:1) to yield two fractions inamounts of 28 mg and 35 mg (total 67%). ¹H NMR (ppm, 200 MHz, CDCl₃) δ2.60 (t, 4H), 2.80 (t, 2H), 3.70 (t, 4H), 4.18 (t, 2H), 7.25-7.50 (m,8H), 7.78 (d, 2H), 8.15 (d, 2H).

Example 75 Preparation ofN-[5-phenyl-4-(phenylhydrazono)-4H-pyrazol-3-yl]nicotinamide

5-Phenyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine (66 mg, 0.25 mmol) wasdissolved in 5 mL of anhydrous methylene chloride. Nicotinoylchloridehydrochloride (50 mg, 0.28 mmol) and triethylamine (78 μL, 0.56 mmol)were added to the solution. Slight fuming of the reaction was noted andthe solution became red. The reaction was stirred at ambient temperaturefor 48 hours. The reaction was filtered to remove a small amount ofwhite solid. To the filtrate was added 30 mL of methylene chloride. Thesolution was washed with 20 mL of a 5% HCl solution. The aqueous layerwas washed with methylene chloride and the combined methylene chloridefractions were washed with water and saturated NaHCO₃ solution. Themethylene chloride solution was dried over MgSO₄, filtered, andevaporated to afford a solid. The material was purified by flashchromatography (CH₂Cl₂:MeOH=15:1) to yield 34 mg (36%) of the titlecompound as a yellow solid. ¹H NMR (ppm, 200 MHz, CDCl₃) δ 7.30-7.55 (m,8H), 7.75 (d, 2H), 8.20-8.30 (m, 2H), 8.55 (d, 1H), 8.81 (d, 1H), 9.45(s, 1H).

Example 76 Preparation of4-(phenylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine

A. Ethyl isonicotinate (7.6 g, 50 mmol) and of acetonitrile (70 mmol)were premixed and added to a suspension of potassium tert-butoxide (5.6g, 50 mmol) in 200 mL of dry toluene at 90° C. This mixture was stirredat this temperature overnight. The solid precipitate was collected byfiltration and dried in vacuo. The product was isolated as the potassiumsalt in a yield of 7.5 g (81%).

B. To a suspension of aniline (0.56 g, 6.0 mmole) in 9.2 mL of water wasadded conc. HCl (1.46 mL, 19 mmol) in an ice bath. NaNO₂ (0.54 g, 8.5mmole) dissolved in water was added to this mixture slowly. Thediazonium solution was then added to the mixture of the potassium saltof 3-oxo-3-pyridin-4-ylpropionitrile (1.5 g, 8.3 mmole) obtained aboveand NaOAc trihydrate (3.5 g, 25.7 mmole) dissolved in 50 mL of water.The precipitate was collected by filtration and dried in vacuo. Theobtained solid was then resuspended in 30 mL of ethanol. Hydrazinehydrate (0.5 mL) was added slowly to this suspension at refluxtemperature and the mixture was refluxed for 3 hours. The title compoundwas obtained after recrystallization from EtOH/hexane (0.49 g, 31%). MS(m/z, ES+): 265 (M+1, 100%).

C. In a similar manner,4-(isoquinolin-5-ylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine wasprepared. 5-Aminoisoquinoline (0.5 g, 3.5 mmol) and potassium salt of3-oxo-3-pyridin-4-ylpropionitrile (1.5 g, 8.3 mmole) yielded 0.089 g ofthe product (8%). ¹H NMR (ppm, 300 MHz, DMSO-d₆) 612.5 (brs, 1H), 9.39(s, 1H), 8.65 (d, 2H), 8.60 (d, 1H), 8.4 (d, 1H), 8.12 (d, 3H), 7.95 (d,1H), 7.79 (t, 1H), 7.45 (br s, 2H); MS (m/z, ES+): 316 (M+1, 30), 158(M−157, 50), 79 (M−236, 100%).

D. In a similar manner,2-{3-[N-(3-amino-5-pyridin-4-ylpyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanolwas prepared. 2-(3-Aminobenzenesulfonyl)ethanol (0.5 g, 2.5 mmol) andpotassium salt of 3-oxo-3-pyridin-4-ylpropionitrile (1.5 g, 8.3 mmole)yielded 0.101 g of the product (13%). MS (m/z, ES+): 373.2 (M+1, 100%).

E. In a similar manner,3-[N′-(3-amino-5-pyridin-4-ylpyrazol-4-ylidene)hydrazino]benzenesulfonamidewas prepared. 3-Aminobenzene-sulfonamide (1.0 g, 5.8 mmol) and potassiumsalt of 3-oxo-3-pyridin-4-ylpropionitrile (1.7 g, 9.4 mmole) yielded0.11 g of the product (6%). MS (m/z, ES+): 344.0 (M+1, 100%).

F. In a similar manner,4-(phthalazin-5-ylhydrazono)-5-pyridin-4-yl-4H-pyrazol-3-ylamine wasprepared. 5-Aminophthalazine (0.25 g, 1.7 mmol) and potassium salt of3-oxo-3-pyridin-4-ylpropionitrile (0.5 g, 2.8 mmole) yielded 0.031 g ofthe product (6%). MS (m/z, ES+): 317.2 (M+1, 25%), 159.0 (M−157, 100%).

G. In a similar manner,4-[(3-morpholin-4-ylmethylphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylaminewas prepared according the procedure described above in Paragraphs A andB with the following modifications: THF was used as the solvent toreplace EtOH and the temperature was 55° C. for the hydrazine reaction.3-Morpholin-4-ylmethylphenylamine (0.192 g, 1.0 mmol) and potassium saltof 3-oxo-3-pyridin-4-ylpropionitrile (0.276 g, 1.5 mmol) yielded 0.117 gof the product (32%). MS (m/z, ES+): 364.4 (M+1. 100%).

H. In a similar manner,5-pyridin-4-yl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine wasprepared. 3-Aminopyridine (0.57 g, 6.0 mmol) and potassium salt of3-oxo-3-pyridin-4-ylpropionitrile (1.5 g, 8.3 mmole) yielded 0.117 g ofthe product (7%). MS (m/z, ES+): 266 (M+1, 65%).

I. In a similar manner,4-[(3-fluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylamine wasprepared. 3-Fluoroaniline (0.6 g, 5.4 mmol) and potassium salt of3-oxo-3-pyridin-4-ylpropionitrile (1.5 g, 8.3 mmole) yielded 0.09 g ofthe product (6%). MS (m/z, ES+): 283 (M+1, 100%).

J. In a similar manner,4-[(3-fluoro-4-methoxyphenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylaminewas prepared. 3-Fluoro-4-methoxyaniline (0.47 g, 3.3 mmol) and potassiumsalt of 3-oxo-3-pyridin-4-ylpropionitrile (1.0 g, 5.5 mmole) yielded0.049 g of the product (5%). MS (m/z, ES+): 313 (M+1, 100%).

K. In a similar manner,4-[(3,4-difluorophenyl)hydrazono]-5-pyridin-4-yl-4H-pyrazol-3-ylaminewas prepared. 3,4-Difluoroaniline (0.31 g, 2.4 mmol) and potassium saltof 3-oxo-3-pyridin-4-ylpropionitrile (1.0 g, 5.5 mmole) yielded 0.071 gof the product (10%). MS (m/z, ES+): 301.4 (M+1, 100%), 287.3 (M−13,40%).

L. In a similar manner,4-[(3,4-difluoro-phenyl)hydrazono]-5-pyridin-3-yl-4H-pyrazol-3-ylaminewas prepared. 3,4-Difluoroaniline (0.31 g, 2.4 mmol) and potassium saltof 3-oxo-3-pyridin-3-ylpropionitrile (1.5 g, 8.3 mmole) yielded 0.044 gof the product (6%). MS (m/z, ES+): 301.4 (M+1, 100%).

M. In a similar manner,4-(phenylhydrazono)-5-pyridin-3-yl-4H-pyrazol-3-ylamine was prepared.Aniline (0.5 g, 5.4 mmol) and potassium salt of3-oxo-3-pyridin-3-ylpropionitrile (1.5 g, 8.3 mmole) yielded 0.21 g ofthe product (15%). MS (m/z, ES+): 265 (M+1, 100%).

N. In a similar manner,5-(2-fluorophenyl)-4-(phthalazin-5-ylhydrazono)-4H-pyrazol-3-ylamine wasprepared. The potassium salt of 3-(2-fluorophenyl)-3-oxo-propionitrilewas prepared from 2-fluorobenzoic acid methyl ester and acetonitrile inthe presence of potassium tert-butoxide. 5-Aminophthalazine (0.25 g, 1.7mmol) and potassium salt of 3-(2-fluorophenyl)-3-oxo-propionitrile (1.5g, 7.5 mmol) yielded 0.022 g of the product (4%). MS (m/z, ES+): 334(M+1, 45%).

O. In a similar manner,4-(phenylhydrazono)-5-thiophen-2-yl-4H-pyrazol-3-ylamine was prepared.Aniline (0.5 g, 5.4 mmol) and 2-theonylacetonitrie (0.5 g, 3.3 mmole)yielded 0.08 g of the product (9%) after recrystallized from EtOH twice.MS (m/z, ES+): 270.8 (M+1, 100%).

P. In a similar manner,5-(3-methoxythiophen-2-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine wasprepared. The potassium salt of3-(3-methoxythiophen-2-yl)-3-oxopropionitrile was prepared from3-methoxythiophene-2-carboxylic acid methyl ester and acetonitril in thepresence of potassium tert-butoxide. Aniline (0.5 g, 3.4 mmol) and thepotassium salt of 3-(3-methoxythiophen-2-yl)-3-oxopropionitrile (0.6 g,7.5 mmol) yielded 0.17 g of the product (17%). MS (m/z, ES+): 300 (M+1,100%).

Example 77 Preparation of 3-morpholin-4-ylmethylphenylamine

A. A solution of 1-bromomethyl-3-nitrobenzene (2.16 g, 10 mmol),morpholine (1.76 g, 20.2 mmol) and triethylamine (1.0 mL) in THF (60 mL)was heated for two hours at 60° C. The solvent was evaporated, water wasadded and the product was isolated by extraction with ether. The etherextract was dried over Mg₂SO₄ and the solvent was evaporated. Thecrystalline residue was used in the next step without furtherpurification. The product, 4-(3-nitrobenzyl)morpholine, was obtained in94% yield (2.09 g).

B. To a solution of 4-(3-nitrobenzyl)morpholine (2.0 g; 9.0 mmol) inTHF/ethanol mixture (1:1, 50 mL) was added a catalytical amount ofRaney-Ni and hydrazine hydrate (36.0 mmol) and the mixture was stirredfor 15 min at ambient temperature, filtered through a celite pad and thefiltrate was evaporated to provide pure3-morpholin-4-ylmethylphenylamine (2.03 g, 98%).

In addition to the foregoing Preparations and Examples, the followingcompounds of the invention were prepared as set forth in the followingExamples.

Example 78 Preparation of 3-Aminopyrazoles

Substituted 3-aminopyrazoles of formulae (C) and/or (D) having atertiary amine in the 5-position (formulae C or D), utilized in ReactionScheme 1, were prepared from substituted 3-methylsulfanylacrylonitrilesaccording to the preparation scheme herein, as known to those ofordinary skill in the art (see, e.g., Hendriksen, Lars Acta Chem. Scand.1996, 50, 432). In this preparation, a cyanoacetate ester of formula (E)and carbon disulfide were reacted together in the presence of a suitablebase such as NaOH. The ester of the resulting intermediate washydrolyzed by reaction in a base such as NaOH, while thio groups werealkylated with a suitable alkylating agent such as dimethyl sulfate. Theintermediate was then purified by recrystallization, affording acompound of formula (F).

The compound of formula (F) was then reacted with a suitablenucleophile, such as a secondary amine, in a solvent such as methanol,forming the substituted 3-methylsulfanylacrylonitrile of formula (G).The compound of formula (G) was then treated with hydrazine, as itshydrate or acid salt, or with a substituted hydrazine in a solvent suchas ethanol, THF, or dioxane to produce the desired substitutedaminopyrazoles of formulae (C) and/or (D). The crude material waspurified by flash chromatography and was then precipitated from anorganic solvent by the addition of an acid such as HCl to afford theproducts of formulae (C) and/or (D) as hydrochloride salts.

Example 79 Preparation of 3-Aminopyrazoles

Substituted 3-aminopyrazoles of formulae (C) and/or (D) having atertiary amine in the 5-position, utilized in Reaction Scheme 1, werealso prepared according to the preparation scheme herein. A substitutedmethylthiopropionitrile of formula (G) was prepared by treating anappropriately substituted cyanoacetamide of formula (H) with a suitablesulfinating reagent such as P₄S₁₀ as reported in the literature (Heyde,C.; Zug, I.; Hartmann, H. Eur. J. Org. Chem. 2000, 19, 3273), to producethe intermediate compound of formula (K). Alternately, the compound offormula (K) can be prepared by reacting the appropriate secondary aminewith a cyanothioacetate of formula (J) (Mueller, H.-G.; Hartke, K. Arch.Pharm. 1988, 321, 879) or a cyanodithioacetate (Wilken, J. et al,Liebigs Ann. Org. Bioorg. Chem., 1996, 6, 927). The compound of formula(K) was then reacted with a suitable methylating reagent in the presenceof a base to afford the substituted methylthiopropionitrile of formula(G) as described in the literature (Vishwakarma, J. N.; Thomas, A.;Apparao, S.; Ila, H.; Junjappa, H. J. Chem. Soc. Perkin Trans. 1, 1988,169). The compound of formula (G) was then further reacted to form3-aminopyrazoles of formulae (C) and/or (D) as described hereinbefore.

Example 80 Preparation of 3-Aminopyrazoles

Substituted 3-aminopyrazoles of formulae (C) and/or (D) having atertiary amine in the 5-position were also prepared according to thepreparation scheme herein. A suitably substituted cyanoacetamide offormula (H) was reacted with triethyloxonium tetrafluoroborate in asuitable solvent such as CH₂Cl₂ followed by the reaction with a suitablebase, such as potassium tert-butoxide, to form the vinyl etherintermediate of formula (L) as described in the literature (Bredereck,H.; et al. Chem. Ber. 1971, 104, 3475). The compound of formula (L) wasthen reacted with hydrazine, as its hydrate or acid salt, or with asubstituted hydrazine in a solvent such as ethanol, THF, or dioxane, toproduce the desired 3-aminopyrazole(s) of formulae (C) and/or (D). Thecrude material was purified by flash chromatography and thenprecipitated from an organic solvent by the addition of an acid such asHCl to afford the product(s) of formulae (C) and/or (D) as ahydrochloride salt.

Example 81 Preparation of 2-Cyano-3,3-bis-methylsulfanyl-acrylic acid

The 2-cyano-3,3-bis-methylsulfanyl-acrylic acid of compound (F) wasprepared as described herein, according to the procedure found in theliterature (Hendriksen, Lars Acta Chem. Scand. 1996, 50, 432). Areaction mixture containing the ethyl cyanoacetate of formula (M) (54mL, 0.5 mol) and carbon disulfide (30 mL, 0.5 mol) in 600 mL of absoluteethanol was cooled to 0° C. A solution of NaOH (40 g, 1 mol) in 40 mL ofwater was added at a rate such that the temperature did not exceed 10°C. Once the addition was complete, the reaction was allowed to warm toambient temperature for 10 minutes and was cooled to 5° C. again. Theresulting precipitate was isolated by filtration, was washed with 100 mLof absolute ethanol and 500 mL of diethyl ether and dried under highvacuum. The synthesis was repeated on the same scale to afford a totalof 259 g (wet weight) of solid compound of formula (N).

The compound of formula (N) (259 g, ˜1 mol) was then introduced to asolution of NaOH (64.4 g, 1.41 mol) dissolved in 455 mL of water. Themixture was heated to 40° C. for 5 hours and was then allowed to cool toambient temperature. The solution was diluted with 820 mL of absoluteethanol. The layers were separated. The lower layer was diluted withwater to a total volume of 1550 mL. This solution was cooled to 5° C.and dimethyl sulfate was added (148 mL, 1.56 mol) at a rate such thatthe temperature could be maintained between 5° C. and 15° C. Once theaddition was complete, the temperature was held at 15° C. for 20 minutesand then between 28-30° C. for 20 minutes. The solution was cooled to15° C. and filtered. The filtrate was acidified with 4N HCl to pH 1.5-2.The resulting solid was isolated by filtration and washed with water.The solid was purified by recrystallization from water. The resultingsolid was isolated by filtration and dried under vacuum to afford 35.0 g(19% yield) of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid, the compoundof formula (F).

Example 82 Preparation of 5-Morpholin-4-yl-2H-pyrazol-3-ylamine

2-Cyano-3,3-bis-methylsulfanyl-acrylic acid (the compound of formula(F), 35 g, 0.18 mol) was dissolved in 250 mL of methanol. Morpholine(the compound of formula (O), 28 mL, 0.32 mol) and triethylamine (25 mL,0.18 mol) were added to the solution while the temperature wasmaintained at approximately 20° C. The reaction was warmed slightly to atemperature of between 25-27° C. and this temperature was maintainedovernight. The solvents were then removed under reduced pressure takingcare not to heat the reaction mixture. The resulting crude material wasfiltered through a short silica gel column eluting with MeOH:CH₂Cl₂=1:5to afford the 3-methylsulfanyl-3-morpholin-4-yl-acrylonitrile of formula(P).

The compound of formula (P) was then dissolved in 100 mL of absoluteethanol and was refluxed with hydrazine hydrate (25 mL, 0.50 mol)overnight. The solvents were removed under reduced pressure and theresulting crude material was purified on a short silica gel columneluting with MeOH:CH₂Cl₂=1:10 to 1:8 to afford a solid. This materialwas further purified by recrystallization from EtOAc/hexanes. The solidwas dissolved in ethanol and concentrated HCl was added to form aprecipitate. The solid was isolated by filtration to yield 9.5 g (26%)of the 5-morpholin-4-yl-2H-pyrazol-3-ylamine of formula (O), as itshydrochloride salt.

The following compounds were also prepared according to the preparationscheme described herein, with the noted exceptions:

-   5-Pyrrolidin-1-yl-2H-pyrazol-3-ylamine hydrochloride (2.2 g),    prepared from the compound of formula (F) (10 g) and pyrrolidine    instead of the compound of formula (O) (8 mL);-   N³,N³-Dimethyl-1H-pyrazole-3,5-diamine hydrochloride (2.3 g),    prepared from the compound of formula (F) (7 g) and dimethylamine    instead of the compound of formula (O) (50 mL of a 2 M solution in    THF);-   5-(4-Methyl-piperazin-1-yl)-2H-pyrazol-3-ylamine (0.4 g), prepared    from the compound of formula (F) (2.8 g) and 4-methylpiperazine    instead of the compound of formula (O) (4.0 mL, with no addition of    triethylamine).

Example 83 Preparation of 3-Pyrrolidin-1-ylmethylphenylamine

A solution of 1-bromomethyl-3-nitrobenzene (the compound of formula (R),5 mmol, 1.08 g), pyrrolidine (11 mmol, 0.79 g), and 1.0 mL triethylamine(the compound of formula NRR′R″ wherein R═R′═R″=ethyl) in THF (35 mL)was heated at 60° C. for 1 hour. The reaction mixture was allowed tocool to ambient temperature overnight with stirring. Water was thenadded to the reaction mixture and the product was extracted into diethylether. The ether layer was dried over sodium sulfate, filtered, andevaporated to yield 1.03 g (94%) of 1-(3-nitro-benzyl)-pyrrolidine (thecompound of formula (S)) which was used in the following reactionwithout further purification.

The compound of formula (S) (1.03 g, 5.0 mmol) was then dissolved in 40mL of a mixture of ethanol:THF (1:1) in a reaction vessel. Hydrazinehydrate (0.5 g, 10 mmol) and a catalytic amount of Raney nickel as aslurry in water were then charged to the reaction vessel. The reactionmixture was stirred at ambient temperature, and the reaction was allowedto proceed to completion as determined by TLC analysis. The reactionmixture was filtered through a pad of silica gel/celite. The pad wasrinsed with ethanol and the ethanol fractions were combined andevaporated to yield 0.76 g (87%) of the title compound of formula (T).

The following compounds were also prepared according to the preparationscheme described herein, with the noted exceptions:

-   3-Dimethylaminomethylphenylamine (0.25 g), prepared from the    compound of formula (R) (0.43 g), and dimethylamine instead of    triethylamine (5 mL of a 2M solution in THF), in the absence of    pyrrolidine;-   3-Morpholin-4-ylmethyl-phenylamine (2.7 g), prepared from the    compound of formula (R) (0.4.3 g), triethylamine (2.0 mL), and    morpholine instead of pyrrolidine (3.5 g).

Example 84 Preparation of 3-Amino-N-methyl-benzenesulfonamide

A reaction vessel charged with 3-nitro-benzenesulfonyl chloride (thecompound of formula (U), 4.42 g, 20.0 mmol) in 150 mL of dry THF at 0°C. was further charged with methylamine (25.0 mL of a 2M solution inTHF, 50 mmol, represented by the formula HNRR′ wherein R═H andR′=methyl). The resulting cloudy solution was stirred overnight atambient temperature. The reaction mixture was then diluted with 150 mLof saturated sodium chloride solution and 50 mL of ethyl acetate. Thelayers were separated and the aqueous phase was extracted twice with 50mL of ethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered, concentrated under reduced pressure. The resultingcrude material was purified by recrystallization from ethanol to yield4.20 g (19.5 mmol) of N-methyl-3-nitrobenzenesulfonamide, the compoundof formula (V) wherein R is methyl.

A reaction vessel charged with the preparedN-methyl-3-nitro-benzenesulfonamide (4.2 g, 19.42 mmol) in 150 ml ofethyl acetate was further charged with 450 mg of 10% palladium oncarbon. The reaction mixture was stirred under hydrogen atmosphere for48 h, then was filtered through a pad of silica gel washing with EtOAc,and the filtrate was concentrated under reduced pressure. The free basewas acidified to give 2.1 g, (˜11 mmol, 58% yield) of the title compound(a compound of formula (W) wherein R is methyl) as its HCl-salt.

The following compound was also prepared according to the preparationscheme described herein, with the noted exceptions:

-   3-Amino-N-(2-hydroxyethyl)-benzenesulfonamide (1.1 g), prepared from    the compound of formula (U) (2.0 g), and ethanolamine instead of    methylamine (2.0 g).

Example 85 Synthesis of Phthalazine-5-ylamine

The 5-nitrophthalazine of formula (Y) was prepared according to priorart literature (Patrick, J.; Ragunathan, R., J. Chem. Soc. Perkin Trans.I, 1993, 211). A reaction vessel charged with phthalazine (the compoundof formula (X), 4.0 g, 30 mmol) in conc. 96% sulfuric acid (30 mL) wasfurther charged with potassium nitrate (14.6 g, 144 mmol) in smallportions. Once the addition was complete, the solution was heated to110° C. overnight. The mixture was then poured over ice and neutralizedwith sodium hydroxide solution resulting in the formation of aprecipitate. The solid was isolated by filtration to yield 2.5 g (47%)of 5-nitrophthalazine of formula (Y) which was used in the followingreaction without further purification.

A reaction vessel was charged with the 5-nitrophthalazine (1.9 g, 10.9mmol) prepared above, dissolved in a mixture of 60 mL of ethanol:THF(5:1). Hydrazine hydrate (2.5 g, 25 mmol) was added to the reactionmixture followed by a catalytic amount of Raney nickel as a slurry inwater. The reaction mixture was stirred at ambient temperature for 4hours. The reaction mixture was then passed through a pad of silicagel/celite which was washed with ethanol. The ethanol fractions werecombined and evaporated to yield 1.2 g (79%) of the title compound offormula (Z).

Example 86 Preparation of 6-Methylpyridin-3-ylamine

The 2-methyl-5-nitropyridine of formula (BB) was prepared according toprior art literature (Odashima, T.; Sakakura, K.; Kohata, K.; Ishii, H.,Bull. Chem. Soc. Jpn., 1993, 66, 797 and references therein). A reactionvessel charged with diethyl malonate (12.5 g, 78.0 mmol) in diethylether (450 mL) was further charged with sodium hydride (3.2 g of a 60%slurry in mineral oil, 79 mmol). When the evolution of hydrogen gassubsided, the 2-chloro-5-nitropyridine of formula (AA) (12.5 g, 79.0mmol) was charged to the vessel with stirring. The solvent was thenremoved by evaporation and the red, tarry residue was heated to 110° C.for 1 hour. At this point, 6 M H₂SO₄ (90 mL) was charged to the vesseland the mixture was heated to reflux overnight. The solution was cooledin an ice bath and was neutralized with potassium hydroxide solution.The solids were removed by filtration and washed with chloroform. Thefiltrate was extracted with chloroform and the combined chloroformfractions were evaporated. The resulting crude material was purified byflash chromatography to yield 6.1 g (56%) of the2-methyl-5-nitropyridine of formula (BB) as a pale orange solid.

A reaction vessel charged with the 2-methyl-5-nitropyridine preparedabove (0.63 g, 4.5 mmol), dissolved in ethanol (30 mL), was furthercharged with hydrazine hydrate (0.3 g, 6.0 mmol) and a catalytic amountof Raney nickel as a slurry in water. The mixture was stirred at ambienttemperature for 2 hours. The solution was then passed through a pad ofsilica gel/celite. The pad was then washed with ethanol and the combinedethanol fractions were evaporated to yield 0.46 g, 94%) of the titlecompound of formula (CC).

Example 87

A. General procedure: The appropriate arylamine or heteroarylamine (1.5mmol) in 3 mL of water was acidified with concentrated HCl (0.5 mL, 6mmol). The resulting solution was cooled to 0° C. and a solution ofsodium nitrite (0.12 g, 1.7 mmol) in approximately 0.5 mL of water wasadded. This mixture was then added to a solution of the appropriate5-substituted 2H-pyrazol-3-ylamine as its free base or its hydrochloridesalt (1.4 mmol) and sodium acetate trihydrate (3.5 g, 25 mmol) in 10 mLof water at 10° C. After 30 minutes, the resulting solid was isolated byfiltration. The crude material was purified by recrystallization or byflash chromatography.

B. The following compounds were prepared similarly to the proceduredescribed above in Paragraph A.

-   4-[(3-Fluoro-phenyl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine    (0.1 g) was prepared from 0.18 g (1.6 mmol) 3-fluoroaniline and 0.23    g (1.4 mmol) 5-morpholin-4-yl-2H-pyrazol-3-ylamine. MS (m/z, ES+):    291.7 (M+1, 100%). Yield=25%;-   5-Morpholin-4-yl-4-(phenyl-hydrazono)-4H-pyrazol-3-ylamine (0.050 g)    was prepared from 0.2 g (2.1 mmol) aniline and 0.25 g (1.5 mmol)    5-morpholin-4-yl-2H-pyrazol-3-ylamine. MS (m/z, ES+): 273.2 (M+1,    100%); ¹H NMR (200 MHz, ppm, DMSO-d₆): δ 11.15 (br s, 1H), 7.6 (d,    2H), 7.45 (t, 2H), 7.25 (t, 1H), 7.15 (br s, 2H), 3.75 (br t, 4H),    3.5 (br s, 4H). Yield=12%;-   4-[(6-Chloropyridin-3-yl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine    (0.012 g) was prepared from 0.05 g (0.4 mmol)    4-amino-2-chloropiridine and 0.03 g (0.18 mmol)    5-morpholin-4-yl-2H-pyrazol-3-ylamine. MS (m/z, ES+): 308.1 (M+1,    100%). Yield=23%;-   5-Morpholin-4-yl-4-(pyridin-3-yl-hydrazono)-4H-pyrazol-3-ylamine    (0.033 g) was prepared from 0.11 g (1.2 mmol) 3-aminopyridine and    0.13 g (0.77 mmol) 5-morpholin-4-yl-2H-pyrazol-3-ylamine. MS (m/z,    ES+): 274.2 (M+1, 100%). Yield=16%;-   5-Morpholin-4-yl-4-(phthalazin-5-yl-hydrazono)-4H-pyrazol-3-ylamine    (0.020 g) was prepared from 0.2 g (1.4 mmol) 5-aminophthalazine and    0.3 g (1.46 mmol) 5-morpholin-4-yl-2H-pyrazol-3-ylamine    hydrochloride. MS (m/z, ES+): 325.1 (M+1, 100%). Yield=4%;-   4-[(3-Fluoro-4-methoxyphenyl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine    (0.38 g) was prepared from 0.30 g (2.1 mmol)    3-fluoro-4-methoxyphenylamine and 0.50 g (2.4 mmol)    5-morpholin-4-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    321.1 (M+1, 100%). Yield=57%;-   3-[N′-(3-Amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide    (0.27 g) was prepared from 0.40 g (2.3 mmol)    3-amino-benzenesulfonamide and 0.50 g (2.4 mmol)    5-morpholin-4-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    352.1 (M+1, 100%). Yield=30%;-   3-[N′-(3-Amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-N-methyl-benzenesulfonamide    (0.11 g) was prepared from 0.45 g (2.4 mmol)    3-amino-N-methyl-benzenesulfonamide and 0.50 g (2.4 mmol)    5-morpholin-4-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    366.1 (M+1, 100%). Yield=13%;-   3-[N′-(3-Amino-5-morpholin-4-yl-pyrazol-4-ylidene)-hydrazino]-N-(2-hydroxyethyl)-benzenesulfonamide    (0.18 g) was prepared from 0.50 g (2.3 mmol)    3-amino-N-(2-hydroxyethyl)-benzenesulfonamide and 0.40 g (2.4 mmol)    5-morpholin-4-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    396.1 (M+1, 100%). Yield=20%;-   4-[(6-Methyl-pyridin-3-yl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine    (0.52 g) was prepared from 0.43 g (3.0 mmol)    6-methylpyridin-3-ylamine hydrochloride and 0.50 g (2.5 mmol)    5-morpholin-4-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    288.1 (M+1, 100%). Yield=60%;-   4-[N′-(3-Amino-5-pyrrolidin-1-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide    (0.021 g) was prepared from 0.28 g (1.6 mmol) 4-aminosulfonamide and    0.19 g (1.0 mmol) 5-morpholin-4-yl-2H-pyrazol-3-ylamine    hydrochloride. MS (m/z, ES+): 336 (M+1, 100%). Yield=6%;-   5-Pyrrolidin-1-yl-4-[(3-trifluoromethyl-phenyl)-hydrazono]-4H-pyrazol-3-ylamine    (0.093 g) was prepared from 0.21 g (1.3 mmol)    3-trifluoromethylphenylamine and 0.20 g (1.1 mmol)    5-pyrrolidin-1-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    325.1 (M+1, 100%). Yield=22%;-   3-[N′-(3-Amino-5-pyrrolidin-1-yl-pyrazol-4-ylidene)-hydrazino]-N-methyl-benzenesulfonamide    (0.13 g) was prepared from 0.29 g (1.3 mmol)    3-amino-N-methyl-benzenesulfonamide and 0.20 g (1.1 mmol)    5-pyrrolidin-1-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    350.1 (M+1, 100%). Yield=28%;-   5-Pyrrolidin-1-yl-4-(quinolin-6-yl-hydrazono)-4H-pyrazol-3-ylamine    (0.074 g) was prepared from 0.19 g (1.3 mmol) 6-aminoquinoline and    0.20 g (1.1 mmol) 5-pyrrolidin-1-yl-2H-pyrazol-3-ylamine    hydrochloride. MS (m/z, ES+): 308.3 (M+1, 100%). Yield=19%;-   3-[N′-(3-Amino-5-pyrrolidin-1-yl-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide    (0.21 g) was prepared from 0.23 g (1.3 mmol)    3-aminobenzenesulfonamide and 0.20 g (1.1 mmol)    5-pyrrolidin-1-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    336.1 (M+1, 100%). Yield=49%;-   4-[(6-Chloro-pyridin-3-yl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine    (0.024 g) was prepared from 0.17 g (1.3 mmol)    6-chloropyridin-3-ylamine and 0.2 g (1.1 mmol)    5-pyrrolidin-1-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    292.5 (M+1, 100%). Yield=6%;-   4-[(3-Fluoro-phenyl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine    (0.070 g) was prepared from 0.15 g (1.3 mmol) 3-fluoroaniline and    0.20 g (1.1 mmol) 5-pyrrolidin-1-yl-2H-pyrazol-3-ylamine    hydrochloride. MS (m/z, ES+): 275.1 (M+1, 100%). Yield=20%;-   5-Pyrrolidin-1-yl-4-[(3-pyrrolidin-1-ylmethyl-phenyl)-hydrazono]-4H-pyrazol-3-ylamine    (0.12 g) was prepared from 0.15 g (0.85 mmol)    3-pyrrolidin-1-ylmethylphenylamine and 0.20 g (1.1 mmol)    5-pyrrolidin-1-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    340.2 (M+1, 100%). Yield=42%;-   4-[(3-Morpholin-4-ylmethyl-phenyl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine    (0.15 g) was prepared from 0.25 g (1.3 mmol)    3-morpholin-4-ylmethylphenylamine and 0.20 g (1.1 mmol)    5-pyrrolidin-1-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    356.2 (M+1, 100%). Yield=33%;-   4-[(6-Fluoro-pyridin-3-yl)-hydrazono]-5-pyrrolidin-1-yl-4H-pyrazol-3-ylamine    (0.030 g) was prepared from 0.16 g (1.0 mmol)    6-fluoro-pyridin-3-ylamine and 0.2 g (1.1 mmol)    5-pyrrolidin-1-yl-2H-pyrazol-3-ylamine hydrochloride. MS (m/z, ES+):    276.1 (M+1, 100%). Yield=11%;-   3-[N′-(3-Amino-5-dimethylamino-pyrazol-4-ylidene)-hydrazino]-benzenesulfonamide    (0.12 g) was prepared from 0.23 g (1.3 mmol) 3-aminosulfonamide and    0.20 g (1.2 mmol) N³,N³-dimethyl-1H-pyrazole-3,5-diamine    hydrochloride. MS (m/z, ES+): 310.1 (M+1, 100%). Yield=30%;-   N,N-Dimethyl-4-(quinolin-6-yl-hydrazono)-4H-pyrazole-3,5-diamine    (0.025 g) was prepared from 0.19 g (1.3 mmol) 6-aminoquinoline and    0.20 g (1.2 mmol) N³,N³-dimethyl-1H-pyrazole-3,5-diamine    hydrochloride. MS (m/z, ES+): 282.1 (M+1, 100%). Yield=7%;-   4-[(6-Chloro-pyridin-3-yl)-hydrazono]-N,N-dimethyl-4H-pyrazole-3,5-diamine    (0.066 g) was prepared from 0.17 g (1.3 mmol)    6-chloropyridin-3-ylamine and 0.2 g (1.2 mmol)    N³,N³-dimethyl-1H-pyrazole-3,5-diamine hydrochloride. MS (m/z, ES+):    266.1 (M+1, 100%). Yield=19%;-   4-[(3-Fluoro-phenyl)-hydrazono]-N,N-dimethyl-4H-pyrazole-3,5-diamine    (0.15 g) was prepared from 0.15 g (1.3 mmol) 3-fluoroaniline and    0.20 g (1.2 mmol) N³,N³-dimethyl-1H-pyrazole-3,5-diamine    hydrochloride. MS (m/z, ES+): 249.1 (M+1, 100%). Yield=45%;-   {3-[N′-(3-Amino-5-dimethylaminopyrazol-4-ylidene)-hydrazino]-5-trifluoromethylphenyl}-methanol    (0.25 g) was prepared from 0.25 g (1.3 mmol)    (3-amino-5-trifluoromethylphenyl)-methanol and 0.20 g (1.2 mmol)    N³,N³-dimethyl-1H-pyrazole-3,5-diamine hydrochloride. MS (m/z, ES+):    329.1 (M+1, 100%). Yield=59%;-   N,N-Dimethyl-4-[(3-morpholin-4-ylmethylphenyl)-hydrazono]-4H-pyrazole-3,5-diamine    (0.14 g) was prepared from 0.25 g (1.3 mmol)    3-morpholin-4-ylmethylphenylamine and 0.20 g (1.2 mmol)    N³,N³-dimethyl-1H-pyrazole-3,5-diamine hydrochloride. MS (m/z, ES+):    330.2 (M+1, 100%). Yield=33%;-   4-[(6-Fluoro-pyridin-3-yl)-hydrazono]-N,N-dimethyl-4H-pyrazole-3,5-diamine    (0.030 g) was prepared from 0.16 g (1.0 mmol)    6-fluoropyridin-3-ylamine and 0.20 g (1.2 mmol)    N³,N³-dimethyl-1H-pyrazole-3,5-diamine hydrochloride. MS (m/z, ES+):    250 (M+1, 100%); Yield=12%;-   4-[(3-Dimethylaminomethylphenyl)-hydrazono]-5-morpholin-4-yl-4H-pyrazol-3-ylamine    (0.030 g) was prepared from 0.16 g (1.0 mmol)    3-dimethylaminomethylphenylamine and 0.20 g (1.2 mmol)    N³,N³-dimethyl-1H-pyrazole-3,5-diamine hydrochloride. MS (m/z, ES+):    330.1 (M+1, 100%). Yield=7%;-   3-[N′-(3-Amino-5-dimethylaminopyrazol-4-ylidene)-hydrazino]-N-methyl-benzenesulfonamide    (0.26 g) was prepared from 0.23 g (1.3 mmol)    3-amino-N-methyl-benzenesulfonamide and 0.35 g (2.15 mmol)    N³,N³-dimethyl-1H-pyrazole-3,5-diamine hydrochloride. MS (m/z, ES+):    324.1 (M+1, 100%). Yield=65%;-   N,N-Dimethyl-4-(pyridin-3-yl-hydrazono)-4H-pyrazole-3,5-diamine    (0.17 g) was prepared from 0.56 g (6.0 mmol)    3-amino-N-methyl-benzenesulfonamide and 0.5 g (3.1 mmol)    N³,N³-dimethyl-1H-pyrazole-3,5-diamine hydrochloride. MS (m/z, ES+):    232.5 (M+1, 100%). Yield=24%;-   N,N-Dimethyl-4-(phthalazin-5-yl-hydrazono)-4H-pyrazole-3,5-diamine    (0.050 g) was prepared from 0.40 g (2.8 mmol) 5-aminophthalazine and    0.40 g (2.4 mmol) N³,N³-dimethyl-1H-pyrazole-3,5-diamine    hydrochloride. MS (m/z, ES+): 283.1 (M+1, 100%). Yield=7%;-   4-{N′-[3-Amino-5-(4-methylpiperazin-1-yl)-pyrazol-4-ylidene]-hydrazino}-benzenesulfonamide    (0.030 g) was prepared from 0.55 g (3.2 mmol) 4-aminosulfonamide and    0.40 g (2.2 mmol) 5-(4-methylpiperazin-1-yl)-2H-pyrazol-3-ylamine.    MS (m/z, ES+): 365.1 (M+1, 100%). Yield=4%;-   5-(4-Methylpiperazin-1-yl)-4-(phenylhydrazono)-4H-pyrazol-3-ylamine    dihydrochloride (0.050 g) was prepared from 0.33 g (3.5 mmol)    aniline and 0.2 g (1.1 mmol)    5-(4-methylpiperazin-1-yl)-2H-pyrazol-3-ylamine. MS (m/z, ES+):    286.1 (M+1, 100%). Yield=16%.

Example 88

This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof:

A. Ingredients % wt./wt. Compound of the invention 20.0% Lactose 79.5%Magnesium stearate 0.5%

The above ingredients are mixed and dispensed into hard-shell gelatincapsules containing 100 mg each, one capsule would approximate a totaldaily dosage.

B. Ingredients % wt./wt. Compound of the invention 20.0% Magnesiumstearate 0.9% Starch 8.6% Lactose 69.6% PVP (polyvinylpyrrolidine) 0.9%

The above ingredients with the exception of the magnesium stearate arecombined and granulated using water as a granulating liquid. Theformulation is then dried, mixed with the magnesium stearate and formedinto tablets with an appropriate tableting machine.

C. Ingredients Compound of the invention 0.1 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80 1.0 g Water q.s. 100 mL

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filtered and bottled.

D. Ingredients % wt./wt. Compound of the invention 20.0% Peanut Oil78.0% Span 60 2.0%

The above ingredients are melted, mixed and filled into soft elasticcapsules.

E. Ingredients % wt./wt. Compound of the invention 1.0% Methyl orcarboxymethyl cellulose 2.0% 0.9% saline q.s. 100 mL

The compound of the invention is dissolved in the cellulose/salinesolution, filtered and bottled for use.

Example 89

This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof:

Ingredients Compound of the invention 0.02 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80 1.0 g 0.9% Saline solutionq.s. 100 mL

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2 m membrane filter andpackaged under sterile conditions.

Example 90

This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof:

Ingredients % wt./wt. Compound of the invention 1.0% Polyethylene glycol1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Example 91

This example illustrates the preparation of a representativepharmaceutical formulation for insufflation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof:

Ingredients % wt./wt. Micronized compound of the invention 1.0%Micronized lactose 99.0%

The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

Example 92

This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof:

Ingredients % wt./wt. Compound of the invention 0.005% Water 89.995%Ethanol 10.000%

The compound of the invention is dissolved in ethanol and blended withwater. The formulation is then packaged in a nebulizer equipped with adosing pump.

Example 93

This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt thereof:

Ingredients % wt./wt. Compound of the invention 0.10% Propellant 11/1298.90% Oleic acid 1.00%

The compound of the invention is dispersed in oleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

The following Examples are directed to various in vitro and in vivoassays which can be utilized by one of ordinary skill in the art todetermine the desired pharmaceutical activity of the compounds of theinvention.

Example 94 In Vitro Screen

Compounds of the invention were screened using a series of diseaserelated kinase targets, such as integrin linked kinase-1. Synthesizedlibraries of compounds are tested against each of the targets to findcompounds that inhibit one of the targets preferentially. The desired invitro potency of the inhibitor is such that the compound is useful as atherapeutic agent, i.e. in the nanomolar or micromolar range.

Inhibition of the targets is measured by scintillation counting; theincorporation of radioactive phosphate onto a specific substrate whichis immobilized onto a filter paper at the end of the assay. To providemeaningful measurements of inhibition, the assays are performed both inthe absence and presence of specific and known inhibitors, and theamount of incorporated radioactivity is compared to provide a baselinemeasurement.

The baseline activity is the amount of radioactivity incorporated in theabsence of inhibitor. The amount of radioactivity incorporated in thepresence of an inhibitor is called the ‘sample activity’, and the %inhibition is expressed by the following formula:% inhibition=100−(sample activity/baseline activity×100)and is usually expressed in conjunction with the compound concentration.By using a range of inhibitor concentrations, the IC₅₀ of an inhibitoris estimated (i.e., the concentration at which enzymatic activity isreduced by 50%). The IC₅₀ of various compounds against a particulartarget can be compared, where a lower IC₅₀ indicates a more potentcompound.Materials and Methods:

Inhibition Assay: Compounds of the invention were lyophilized and storedat −20° C. Stock solutions were made by weighing out the compounds anddissolving them in dimethyl sulfoxide (DMSO) to a standardconcentration, usually 20 mM, and stored at −20° C. The compounds werediluted to a starting intermediate concentration of 250 μM in 1% DMSO,then serially diluted across a row of a 96 well plate using serial 2fold dilution steps. Diluted 100% DMSO was used as a negative control.

5 μl of each compound dilution were robotically pipetted to Costarserocluster plates maintaining the same plate format. All assaysconsisted of the following volumes:

-   -   5 μl diluted compound    -   10 μl enzyme preparation    -   5 μl substrate    -   5 μl assay ATP        and were then incubated 15 minutes at ambient temperature.

From each reaction, 10 μl of reaction mix was spotted onto MilliporeMultiscreen-PH opaque plates and washed 2×10 minutes in 1% phosphoricacid. The plates were dried for at 40° C. for 30 min, then the substratephosphate complexes were quantitated by scintillation counting. TheseMillipore plates are in a 96 well format with immobilized P81phosphocellulose membranes. Both the phosphorylated andnon-phosphorylated form of the substrate bind to the membrane while ATP(unincorporated phosphate) is removed in the subsequent wash steps.Results are shown in Table 1 below.

Integrin Linked Kinase: The target integrin linked kinase is afull-length recombinant protein expressed in sF9 insect cells bybaculovirus infection. The ILK1 substrate is CKRRRLASLR-amide.

Recombinant ILK protein was expressed using cultured insect cells and abaculovirus expression system. Standard techniques for DNA manipulationwere used to produce recombinant DNA molecules and baculoviruses(Sambrook. J., Fritsch, E. F. and Maniatis, T. 1989, Molecular cloning,a laboratory manual. Second edition. Cold Spring Harbor LaboratoryPress. NY; Crossen, R. and Gruenwald, S. 1998. Baculovirus expressionVector System Manual. 5^(th) Edition. Pharmingen, San Diego, Calif.) butthe isolation of active ILK required some ingenuity.

The ILK open reading frame (Hannigan et al., supra.), excluding the 5′and 3′ untranslated regions, was inserted into the baculovirus transfervector pAcG2T (Pharmingen) to produce a GST fusion protein under thecontrol of the strong AcNPV polyhedrin promoter. A large scale plasmidpreparation of the resulting transfer construct was made using a QiagenPlasmid Midi Kit. This ILK transfer construct was then co-transfectedwith BaculoGold DNA (Pharmingen) into Sf9 insect cells (Invitrogen) anda high titre preparation of GST-ILK recombinant baculovirus was producedby amplification in Sf9 cells. Liter scale expression of GST-ILKrecombinant protein was done in 1000 mL spinner flasks (Bellco) byinfection of Hi5 insect cells (Invitrogen) grown in Ex-Cell 400 SerumFree Media (JRH Biosciences) at a multiplicity of infection ofapproximately 5. The cells were harvested three days after infection andlysed in Hypotonic Lysis Buffer (HLB; 10 mM imidazole, 5 mM EDTA, 0.1%β-mercaptoethanol, 10 μg/mL PMSF, 1 mM benzamidine) by sonication. Thelysate was centrifuged at 10,000 g for 20 minutes and the supernatantwas discarded. The pellet was washed twice in HLB and then washed twicein High Salt Buffer (“HSB”; 500 mM NaCl, 10 mM imidazole, 5 mM EDTA,0.1% β-mercaptoethanol, 10 μg/ml PMSF, 1 mM benzamidine). The pellet wasthen resuspended in DNAse-ATP Buffer (“DAB”; 10 mM MgCl₂, 1 mM MnCl₂,β-methyl aspartic acid, 2 mM NaF, 0.55 mg/mL ATP, 1 μg/mL DNAse I, 1%NP40, 10 mM imidazole, 5 mM EDTA, 0.1% β-mercaptoethanol, 10 μg/mL PMSF,1 mM benzamidine) and stirred for 30 minutes at ambient temperature, andthen centrifuged at 10,000×g for 20 min. The pellet was resuspended inHigh Salt Detergent buffer (“HDB”; 1% NP40, 1% Triton X-100, 500 mMNaCl, 10 mM imidazole, 5 mM EDTA, 0.1% β-mercaptoethanol, 10 μg/mL PMSF,1 mM benzamidine), stirred for 30 minutes at ambient temperature, andthen centrufuged at 10,000 g for 20 min. The pellet was then washed oncein each of HDB, HSB, and HLB, centrifuging at 10,000 g each time.Finally, the pellet was resuspended in HLB.

The recombinant ILK expressed in insect cells with a baculovirus systemwas solubilized by treating the insoluble ILK protein with DNAse I anddetergents. This produced an ILK protein preparation in the form of amicroparticle suspension. This preparation had a high specific activityand was amenable to automated kinase assays.

The compounds of the invention, when tested in the above assay,demonstrated the ability to inhibit ILK.

Example 95 Western Blot Analysis of Phospho-PKB/Akt

The phospho-PKB/Akt Ser473 status of tumor cells was determined byWestern blotting of cell lysates. PC3 tumor cells were grown to 60-80%confluency in complete media (DMEM with 10% fetal bovine serum). On dayone, the cells were trypsinized, washed and resuspended in completemedia at a concentration of 4×10⁴ cells/mL. Then, 2 mL/well of thissuspension was seeded into a six-well plate and incubated overnight at37° C. and 5% CO₂. The objective was to obtain cells at about 40%confluency in 24 hours and 60-80% confluency after 48 hours of growth.On day two, the cells were checked for complete adherence. Then themedia was aspirated from each well and replaced with serum free media(DMEM only). The plates were incubated at 37° C. and 5% CO₂ overnightagain. On day 3, media was aspirated from each well again, replaced withserum free media, and test compound treatments were added. Testcompounds (i.e., compounds of the invention) were made up as 20 mM 100%DMSO stocks and these are diluted to 2 mM working solutions in serumfree media. Then, the 2 mM working solutions were diluted to a finaltreatment concentration of 12.5 μM by adding 12.5 μL to 2 mL of media inthe 6-well plates. The treated plates were incubated at 37° C. and 5%CO₂ for 3 hours.

Treated cells in 6-well plates were put on a sloped bed of ice and themedia was aspirated off. The cells were rinsed with 500 μL of ice coldphosphate buffered saline, and this was aspirated again. Then, 200 μL ofSDS PAGE sample buffer (2% sodium docecyl sulfate, 62.5 μM Tris pH 6.8,10% glycerol, 5% β-mercaptoethanol, 0.0025% bromophenol blue) was addedand cells were scraped with a rubber-tipped cell scraper. The lysateswere transferred into a 1.7 mL microfuge tube and stored frozen at −20°C. The SDS PAGE procedure was carried out on a Hoefer SE600electrophoresis system. The frozen cell lysates were denatured for 5minutes in a boiling water bath and pulse centrifuged for 10 seconds.Approximately 80 μL or 20 μg of total protein was loaded into a 15-well11×15 cm 10% acrylamide separating gel. Equal sample loading wasaccomplished by pilot experiments to verify amount and consistency ofprotein loading by Western blotting with the nonphospho proteinantibody. The gel was run overnight at ambient temperature in 1× runningbuffer (15% glycine, 1% SDS, 25 mM Tris base) with 9 mA applied. Thenthe gel was transferred to nitrocellulose in a Transphor apparatus with1× transfer buffer (9% glycine, 20 mM Tris base) at a current of 400 mAfor 3 hours at 4° C.

The membrane was blocked for 1 hour at ambient temperature in blockingsolution (5% nonfat dry skim milk powder in 20 μM Tris, 250 μM NaCl,0.05% Tween). The blot was then washed 3 times for 5 minutes each inTTBS (20 μM Tris, 250 μM NaCl, 0.05% Tween), then incubated overnight at4° C. with primary antibody polyclonal phospho-PKB/Akt Ser473 diluted1:750 in TTBS. The membrane was then washed 3 times for 5 minutes eachat ambient temperature with TTBS. The blot was then incubated withsecondary antibody goat anti-rabbit HRP conjugated IgG diluted 1:5000 inTTBS for 45 minutes at ambient temperature, followed by one quick TTBSrinse, another 2 washes for 15 minutes each in TTBS, and a final 20minutes wash in TBS. To image the membrane, it was placed into freshlyprepared ECL solution, sandwiched in clear plastic wrap, and exposed tofilm for 30 secends to 10 minutes, depending upon the strength of theluminescence signal. The film was then developed. The image was recordedand quantitated using BioRad's Gel Doc 1000 camera system andMulti-analyst Version 1.1 software. The calculation of %Inhibition=100−[(density of test treatment/density of DMSOtreatment)×100].

See Dryer R. L. and Latta G. F. (1989) “Experiental Biochemistry” NewYork: Oxford University Press; and Laemmli U.K. (1970) “Cleavage ofstructural proteins during the assembly of the head of bacteriophage T4”Nature 227(259):680-5 for additional discussion of the use of WesternBlot analysis.

Example 96 Inhibition of Nitric Oxide and Cytokine Release

Macrophages isolated from the murine peritoneal cavity are a suitablesample for studying the activation properties of this immunologicallyimportant cell type. Macrophages are important in natural resistance toinfection and are among the first cells to be exposed to infectiousagents and become activated. Lipopolysaccharide (LPS) and interferongamma (IFN-γ) are potent activators of macrophages, priming them for avariety of biological effects. These biological effects are mediated inpart by the release of nitric oxide (NO) and the increased production ofpro-inflammatory cytokines. Peritoneal exudate macrophages were isolatedby peritoneal lavage with ice-cold sterile physiological saline 24 hoursafter intraperitoneal injection of BALB/c and CB57BL/6 mice with 0.3 mlof sterile Zymosan A (1 mg/0.5 mL 0.9% saline). Cells were washed,resuspended in RPMI 1640 supplemented with 2 mM L-glutamine, 100units/mL penicillin, 100 μg/mL streptomycin, and 5% FBS. 1.5×10⁵cells/well were seeded in 96-well plates and followed by 3 hourincubation at 37° C. with 5% CO₂ (macrophages were allowed to attach)cells were stimulated with LPS (0.5 mg/mL) and IFN-γ (100 U/mL) in theabsence or presence of the test compounds. All treatments werereplicated six times. Cells were incubated for an additional 24 hours,and cell free culture supernatants from each well were collected for NOand cytokine determination. The remaining cells were stained withcrystal violet to determine effect of the compound on cell survival.

For a discussion of the stimulation of primary mouse peritonealmacrophages for NO and cytokine determination see, e.g., Calandra T.,Spiegel L. A., Metz C. N., and Bucala R. “Macrophage migrationinhibitory factor is a critical mediator of the activation of immunecells by exotoxins of Gram-positive bacteria” Proc Natl Acad Sci USA(1998) 95(19): 11383-8; Lu L., Bonham C. A., Chambers F. G., Watkins S.C., Hoffman R. A., Simmons R. L., and Thomson A. W. “Induction of nitricoxide synthase in mouse dendritic cells by IFN-gamma, endotoxin, andinteraction with allogeneic T cells: nitric oxide production isassociated with dendritic cell apoptosis” J. Immunol. (1996) 157(8):3577-86; Keil D. E., Luebke R. W., and Pruett S. B. “Differences in theeffects of dexamethasone on macrophage nitrite production: dependence onexposure regimen (in vivo or in vitro) and activation stimuli” Int J.Immunopharmaco (1995) 17(3): 157-66; and Skeen M. J., Miller M. A.,Shinnick T. M., and Ziegler H. K. “Regulation of murine macrophage IL-12production. Activation of macrophages in vivo, restimulation in vitro,and modulation by other cytokines” J. Immunol. (1996) 156(3): 1196-206.

Inhibition of NO Release Determination:

The production of NO was determined by assaying culture supernatants forNO₂ ⁻, a stable reaction product of NO with molecular oxygen. Briefly,100 μL of culture supernatant was reacted with an equal volume of Griessreagent at ambient temperature for 10 minutes. The absorbance at 550 nmwas determined. All measurements were performed six times. Theconcentration of NO2- was calculated by comparison with a standard curveprepared using NaNO2.

For discussion of measuring nitric oxide in tissue culture supernatants,see, e.g., Amano F., and Noda T. “Improved detection of nitric oxideradical (NO) production in an activated macrophage culture with aradical scavenger, carboxy PTIO and Griess reagent” FEBS Lett. (1995)368(3): 425-8; Archer S. “Measurement of Nitric oxide in biologicalmodels” (1993) FASEB J. 7:349-360; Arima H., Nishimoto Y., Motoyama K.,Hirayama F., and Uekama K. “Inhibitory effects of novel hydrophiliccyclodextrin derivatives on nitric oxide production in macrophagesstimulated with lipopolysaccharide” Pharm Res. (2001) 18(8):1167-73; KimY. M., and Son K. “A nitric oxide production bioassay forinterferon-gamma” J. Immunol Methods. (1996) 198(2):203-9; and Patel R.,Attur M. G., Dave M. N., Kumar S., Lee J. C., Abramson S. B., and AminA. R. “Regulation of nitric oxide and prostaglandin E2 production byCSAIDS (SB203580) in murine macrophages and bovine chondrocytesstimulated with LPS” Inflamm Res. (1999) 48(6):337-43.

Inhibition of IL-12 Release Determination:

Murine primary macrophage will get activated following incubation withLPS in the presence of sub-optimal doses of IFN-γ. Upon activation,macrophages participate actively in the onset of inflammation byreleasing bioactive molecules that amplify the initial inflammatoryresponse. Stimulated macrophages demonstrate up-regulated expression ofMHC-II receptors, increased release of NO and produce a number ofpro-inflammatory cytokines including IL-12, IL-6, TNF-α, MIP-1α andMIP-1β.

Briefly, IL-12 levels in the supernatants from stimulated macrophageswere determined with PharMingen's OptEIA ELISA set developed using ananti-mouse IL-12 Ab pair and mouse rIL-12 standard (PharMingen).Maxisorp F16 multiwell strips (Nunc, Roskilde, Denmark) were coated withanti-mouse IL-12 capture Ab (at recommended concentration) in 0.1 MNaHCO₃, pH 9.5, 100 μL/well, overnight at 4° C. Plates were washed threetimes with 0.05% Tween 20 in PBS (PBST) and blocked for 1 hour atambient temperature with 200 mL/well of 10% FCS in PBS (blocking anddilution buffer). Plates were washed three times with PBST and duplicatesamples (100 μL/well) or standards (100 μL/well) in diluent buffer wereincubated for 2 hours at ambient temperature. Plates were washed fivetimes with PBST and incubated with biotinylated anti-mouse IL-12 andavidin-horseradish peroxidase conjugate (at concentrations recommendedby the manufacturer) for 1 hour at ambient temperature. Plates werewashed seven times with PBST and 100 μL of3,3′,5,5′-tetramethylbenzidine substrate solution was added to eachwell. After 15-30 minute incubation at ambient temperature, colordevelopment was terminated by adding 50 μL of 2 N H₂SO₄. Absorbance wasread at 450 nm with an EL 312e microplate reader. The detection limitfor IL-12 was 15.6 pg/ml.

For discussion of measuring Interleukin-12 (IL-12) in tissue culturesupernatants, see, e.g., Skeen M. J., Miller M. A., Shinnick T. M., andZiegler H. K. “Regulation of murine macrophage IL-12 production,Activation of macrophages in vivo, restimulation in vitro, andmodulation by other cytokines” J. Immunol. (1996) 156(3):1196-206.

Example 97 In Vitro Angiogenesis Assay

Angiogenesis, the formation of new blood vessels from pre-existingendothelium, is a critical process involved in numerous physiologicaland pathological conditions. Disruption of this tightly regulatedprocess has been implicated in both chronic inflammation and solidtumour growth. The matrigel morphogenesis assay is an in vitro modelused to mimic the process by which endothelial cells form capillaries invivo. Human umbilical vein endothelial cells (HUVECs) were plated overmatrigel, a complex mixture of solubilized basement membrane components,and cultured in serum poor medium with specific growth factors and inthe presence of the test compound. HUVEC cells cultured for 24 hours inM199 with 0.5% FCS were plated at 6×10⁵ cells/well in 12-well platespre-coated with 300 μL of Matrigel (10.7 mg/mL) in M199 with 0.5% FCS inthe presence of VEGF (1 ng/mL), and in the absence or presence of thetest compounds. After 5 hours of incubation in a 5% CO₂-humidifiedatmosphere at 37° C., the three-dimensional organization of the cells(the capillary-like structures) was examined using an invertedphotomicroscope. The cells were fixed with crystal violet (0.05% in 20%ethanol) and photographed using a digital camera. Qualitative analysiswas accomplished by comparing the pattern, size and integrity of thevessels formed in the test wells with those of the VEGF control wells.Quantitative analysis was performed on the images collected using theImage-Pro Plus software program.

For further discussion regarding in vitro angiogenesis assay, see, e.g.,Grant D. S., Lelkes P. I., Fukuda K., and Kleinman H. K. “Intracellularmechanisms involved in basement membrane induced blood vesseldifferentiation in vitro” In Vitro Cell Dev Biol. (1991) 27A(4):327-36;Kubota Y., Kleinman H. K., Martin G. R., and Lawley T. J. “Role oflaminin and basement membrane in the morphological differentiation ofhuman endothelial cells into capillary-like structures” J. Cell Biol.(1988) 107(4):1589-98; Passaniti A., Taylor R. M., Pili R., Guo Y., LongP. V., Haney A., Pauly R. R., Grant D. S., and Martin G. R. “A simple,quantitative method for assessing angiogenesis and antiangiogenic agentsusing reconstituted basement membrane, heparin, and fibroblast growthfactor” (1992) Lab. Invest. 67:519-528; and Salani, D., Taraboletti, G.,Rosano, L., Di Castro, V., Borsotti, P., Giavazzi, R., and Bagnato, A.,“Endothelin-1 induces an angiogenic phenotype in culture cells andstimulates neovascularization” In Vivo. Am. J. of Pathol. (2000)157(5):1703-1711.

Example 98 Tumor Cell Invasion Assay

Tumor cell invasion was assayed using a modified Boyden chamber 24-wellcell culture plate. The chambers were constructed with a porous membranedividing a top and bottom chamber. An additional thin Matrigel(extracellular matrix extract) layer on top of the membrane was used sothat the tumor cells must move through the Matrigel and the membranebefore entering the bottom chamber. Tumor cells were plated into the topchamber in serum free media, and allowed to move to the bottom chamberwhich contained fibroblast conditioned media as an attractant.

The invasion assays were carried out using BD BioCoat FluoroBlokInvasion plates. The plates were first warmed to ambient temperaturefrom −20° C. storage and the matrigel layer was rehydrated with 0.5 mLof 37° C. phosphate buffered saline added to the top chambers. Theplates were incubated at 37° C. in normal atmosphere for 2 hours. Thenthe PBS rehydrant was carefully removed from the top chamber just beforeuse. Before the assay was carried out, fibroblast conditioned media wasproduced by seeding 3×10⁶ cells of NIH 3T3 into 30 mL of media in a T150cell culture flask and grown at 37° C. and 5% CO₂ for 72 hours. Themedia was harvested by centrifuging at 1800×g for 10 minutes (Eppendorf5810), aliquoted into 10 mL portions, and stored at −20° C.

The test compound solution was prepared by diluting the 20 mM stocksolution in 100% DMSO with serum free media to a final concentration of500 μM or 250 μM. Tumor cells DU-145 were grown to 50-70% confluency incomplete media (DMEM with 10% fetal bovine serum). On the day of theassay the cells were trypsinized, washed and resuspended in serum freemedia (DMEM) at a concentration of 1×10⁶ cells/mL. Then 450 μL of thiscell suspension was added to the top chamber plus 50 μL of the testcompound solution to yield the final concentration of 50 or 25 μM. Thesolution containing the equivalent amount of DMSO as in the testcompound treatment was used as the negative control. Each treatment wasdone in duplicate. Into the bottom chambers were added 750 μL of 50%complete media and 50% fibroblast conditioned media. These plates wereincubated at 37° C. and 5% CO₂ for 24 hours.

The degree of tumor cell invasion was measured by first staining thecells with the fluorescent dye, calcein AM, and then measuring thefluorescence in a plate reading fluorometer as follows: After the 24hour incubation, the invasion top plate was transferred to a new bottomplate containing 0.5 mL of Hanks buffered salt solution with 5 μg/mL ofcalcein AM and then incubated for 1 hour at 37° C. and 5% CO₂.Fluoresence in each well was determined on a Fluoroskan Ascent FL(Labsystems) on bottom read with excitation/emission wavelengths of485/538 nm and was expressed as relative fluorescence units (RFU). Thepercent inhibition of invasion was calculated from these RFU's using theformula: % Inhibition=100−(RFU of test treatment/RFU of DMSOtreatment)×100.

See, e.g., Crouch M. F. (2000) “An automated fluorescence based assay ofneurite formation” J. Neurosci Methods 104(1):87-91; and Repesh L. A.(1989) “A new in vitro assay for quantitating tumor cell invasion”Invasion Metastasis 9(3):192-208 for additional discussion aboutinvasion and migration assays.

Example 99 Tumor Cell Migration Assay

Tumor cell migration assay was conducted in the similar way as describedin Example 96 except that the plates used were constructed with only aporous membrane dividing a top and bottom chamber without the additionalthin matrigel (extracellular matrix extract) layer on top of themembrane (BD Fluoroblock plates). The percent inhibition of migrationwas determined in the same way as illustrated in Example 96.

See, e.g., Crouch M. F. (2000) “An automated fluorescence based assay ofneurite formation” J. Neurosci Methods 104(1):87-91; and Repesh L. A.(1989) “A new in vitro assay for quantitating tumor cell invasion”Invasion Metastasis 9(3):192-208 for additional discussion aboutinvasion and migration assays.

Example 100 Irritant Contact Dermatitis Model (ICD)

Female Balb/c (H2-^(d)) mice were used in this experiment (n=8). ICD wasinduced with phorbol 12-myristate 13-acetate (PMA), 4 μg/ear (in 20 μLacetone). Dexamethasone was used as a positive control (0.5 mg/kg) andwas administered s.c. in 50 mL volume prior to irritation. The irritantwas painted onto the dorsal side of the right ear pinna. The testcompounds were delivered via oral gavage at a dose between 50-300 mg/kg(10 mL/kg). Ear thickness was measured with a spring-loaded dialmicrometer before irritation and at 3, 6 and 24 hours after painting theirritant. The efficacy of the anti-inflammatory effect of the testcompounds was determined by comparison of the thickness of the inflamedear and the control ear.

Example 101 PMN Model (Chemotaxis)

In each experiment Balb/c mice (females, n=30) were used. All mice wereinjected intraperitoneally with Zymosan (1 mg/0.5 mL saline). The testcompound was delivered via oral gavage at a dose of 200 mg/kg (10 mL/kg)one hour prior and one hour post Zymosan injection. Mice were euthanized(asphyxiation with CO₂) 4 hours after Zymosan administration, and theabdomen was swabbed with 70% ethanol. The peritoneal skin was retractedback to expose the underlying muscle layer. Peritoneal polymorphonuclearleukocytes (PMN) were collected by flushing the peritoneal cavity with10 mL of ice-cold PBS containing 1% FBS. After gentle agitation of theabdomen, the peritoneal lavage samples will be withdrawn and transferredto pre-labelled tubes (the tubes were kept on ice). The efficacy of theanti-inflammatory effect of the test compounds was evaluated bydetermining the change in number of recruited polimorphonuclear cells. Adecreased number of recruited PMN indicated reduced in vivo migration ofneutrophils and correlated with the anti-inflammatory effect of the testcompounds.

For additional discussion regarding Zymosan induced peritonitis, see,e.g., Ajuebor M. N., Flower R. J., Hannon R., Christie M., Bowers K.,Verity A., and Perretti M. “Endogenous monocyte chemoattractantprotein-1 recruits monocytes in the zymosan peritonitis model” J. LeukocBiol. (1998) 63(1):108-16; Getting S. J., Flower R. J., and Perretti M.“Inhibition of neutrophil and monocyte recruitment by endogenous andexogenous lipocortin 1” Br. J. Pharmacol. (1997) 120(6):1075-82;Nakamura S., Yoshinaga M., and Hayashi H. “Interaction betweenlymphocytes and inflammatory exudate cells. II. A proteolytic enzymereleased by PMN as a possible mediator for enhancement of thymocyteresponse” J. Immunol. (197.6) 117(1):1-6; and Whelan J., Broughton K.S., Lokesh B., and Kinsella J. E. “In vivo formation of leukotriene E5by murine peritoneal cells” Prostaglandins (1991) 41(1):29-42.

Example 102 Orthotopic Lung Model

Materials and Methods:

Cell Implantation for donor tumors: NCI-H460 human lung large cellcarcinoma cells were harvested by trypsinization and adjusted to a finalconcentration of 1×10⁶ cells/80 mL. Male nude rats (CR:NIH-RNU) wereendobronchially implanted with 1×10⁶ tumor cells using a 20 gauge, 2inch Teflon catheter passed into the right caudal lobe via a smalltracheotomy incision.

Implantation of tumor fragments: These tumor-bearing rats weresacrificed at three weeks following implantation and their tumorsharvested in cold RPMI 1640. Viable tumor was cut into 1-2 mm diameterpieces by “crossed scalpels” technique. A 50 mg portion was placed intoa 16 gauge, 2 inch Teflon catheter and implanted into 6-week-old malenude rats using a similar technique. Animals were treated with Augmentinat 0.35 mg/mL in water for 2 weeks.

Preparation of agents: The test compound was prepared fresh each day bydissolving it in an acceptable recipient at 10 mg/mL under sterileconditions. Cisplatin injection, 1 mg/mL, was obtained from the hospitalpharmacy.

Study Design: There were four arms in the study: control; test compoundalone; cisplatin alone; test compound and cisplatin combination. Also,there were two groups in the study: in group I, all animals werefollowed until death to assess maximum length of survival and in groupII, all animals were simultaneously sacrificed from each treatment armas control animals became severely cachectic or died. This allows us todirectly compare, at the same point in time, the therapeutic effects ofeach study arm on tumor related endpoints, such as primary tumor weight,tumor/body weight ratio, mediastinal lymph node weight and metastaticpattern. Renal and liver functions of each animal were also examined byserum biochemistry to assess possible toxicities.

Both test compound (5 mg daily) and cisplatin (5 mg/kg weekly for 3weeks) were administered by intraperitoneal injection. Treatmentcommenced 7 days and 14 days post implantation for the test compound andcisplatin, respectively. Animals were sacrificed when they showed signsof significant morbidity or impending death. At necropsy the heart-lungblocks, kidney, brain, and chest wall were removed, serially sectioned,stained with H & E, and examined in a blinded fashion by a pathologist.

Statistical Analysis: Statistical analysis for length of survival,primary tumor, body, and mediastinal lymph node weight were evaluatedusing ANOVA or unpaired Student's t-test. Incidence of metastasis wasevaluated by using a contingency table with Fisher's exact test.Differences of P<0.05 were considered to be significant.Immunocytochemistry. The H-460 cell line was seeded into 8-chamberslides (10⁴ cells/well) and treated with 25 uM of the test compoundafter reaching a confluency of 60 to 80%. Cells were harvested at 2, 4,8 and 24 hours after treatment and incubated overnight at 4° C. with theprimary antibodies. For phosphorylated Akt/PKB expressionanti-phospho-Akt/PKB (Ser-473), was used at a concentration of 2 μg/mL,followed by incubation with the secondary antibody, biotinylatedrabbit-IgG at a concentration of 7 μg/mL. For phosphorylated GSK-3βexpression anti-phospho-GSK-3β (Ser-9), a concentration of 6 μg/mL wasused, followed by incubation with the same secondary antibody.Streptavidin-peroxidase was used as a detection system. DAB was used aschromogen and counterstaining was performed with hematoxylin. Slideswere assessed as either positive or negative according to the amount andintensity of staining. Phospho-Akt/PKB and phospho-GSK-3β reactivity wasquantitated by computerized image analysis using an Image-Pro system andconventional light microscopy.

Example 103 ILK Expression is High in Human Psoriatic Skin as Comparedto Normal Skin

Psoriasis is a complex inflammatory autoimmune condition characterizedby an abnormal activation of skin T lymphocytes, dermal and epidermalinfiltration by various types of leukocytes, hyper-proliferation ofkeratinocytes and pronounced angiogenic activity within the dermalvasculature. The thickness of the epidermal layer within psoriaticplaques is dramatically greater than that of normal skin of healthyindividuals or the uninvolved skin of the psoriasis patient.

To test for ILK expression, skin samples were obtained from a humansubject with healthy skin and from patients suffering from theimmune-mediated condition psoriasis. Skin preparations were processedusing routine formalin-fixation and paraffin embedding techniques.Sections were cut and treated with antigen retrieval methodology andstained with a rabbit anti-ILK polyclonal antibody (catalogue #06-592,Upstate Biotechnology, Lake Placid N.Y.). Sections were then incubatedwith peroxidase-conjugated goat anti-rabbit polyconal antibody. Slideswere then developed using standard techniques.

In normal skin, a low level of ILK expression was evident in thesupra-basal layers of skin keratinocytes. These supra-basal layers ofskin keratinocytes were almost certainly undergoing the process ofterminal differentiation. The staining intensity for ILK was moreintense for keratinocytes near the outer keratin layer. Little or no ILKstaining was observed for the dermal vascular endothelium. In contrast,staining for ILK was highly intense for the hyper-proliferativekeratinocytes within the plaques of patients with psoriasis patients.Within the dermal region of psoriatic patient plaques, cells comprisingthe vasculature stained strongly for ILK. Further, some of theinflammatory cells present within the dermal region stained positivelyfor ILK. Overall, in contrast to normal skin, ILK was expressed at muchhigher levels within the epidermal and dermal regions within skinplaques of patients with psoriasis.

Example 104 Expression of ILK in Psoriatic Tissue Correlates withSeverity of Disease

The expression of ILK within psoriatic skin was evaluated for a seriesof plaque biopsy samples obtained from a patient over a 3-month period.The presence and expression pattern of ILK was evaluated byimmunohistological analyses. All sections were stained at the same time.For psoriasis, the disease-state can be gauged by the relative thicknessof the epidermis. For the series of biopsy samples evaluated, expressionlevels of ILK closely paralleled the psoriasis disease-state at thetissue level.

The first sample (panel A), was obtained at screening while the patientwas experiencing active disease. Staining for ILK was intense for thekeratinocytes within the target plaque. Within the dermal region of theplaque, cells within the vasculature as well as cells that hadinfiltrated the region also stained strongly for ILK. The second sample(panel B) was obtained one month later, a time when disease activity hadfurther intensified. ILK staining intensity with this sample was muchstronger than for the first sample. The third sample was takenapproximately 4 weeks after sample B, a time during which this subjectwas exhibiting an improvement in their disease and a reduction inepidermal thickness. For this sample (panel C) there was a correspondentreduction in ILK staining intensity, both for the epidermalkeratinocytes and within cells of the dermal vasculature. Sample 4 wasobtained 3 months after sample 1, at a time when the subject wasexperiencing a flare in disease activity. Epidermal thickness for sample4 was greater than that of sample 3. At this time, an increase in ILKstaining intensity was evident within the dermal vasculature andcellular infiltrate as well as for the epidermal keratinocytes (panelD). Thus, expression levels of ILK within the psoriatic plaque variedwith disease activity with high ILK expression correlating with symptomsof active disease.

Example 105 Anti-inflammatory Effect of ILK-inhibition

The anti-inflammatory activity of a compound of the invention wasdemonstrated in an acute mouse ear-swelling edema model. To induce thisinflammatory experimental condition, mice are treated topically on thesurface of an ear with tetra phorbol ester (TPA). Application of TPA insuch a manner produces a rapid increase in ear thickness caused by fluidbuildup and the infiltration of the tissue by inflammatory cells.

Different doses of a compound of the invention were given orally at thesame time as an active amount of TPA. Ear measurements performed 6 hoursafter these treatments showed that a dose of a compound of the inventionof 200 mg/kg almost completely prevented the increase in ear swellingstimulated by TPA. The effect of this dose of a compound of theinvention on this response was comparable to that produced bydexamethasone, a well-characterized and potent anti-inflammatory agent.Thus, a compound that is known to inhibit the activity of ILK in vitrocan also affect the development of symptoms of an experimentalinflammatory skin condition in vivo.

Example 106 Demonstration of ILK Inhibition as Therapeutic Interventionin Renal Disorders

Methods:

Mice transgenic for the bovine growth hormone (GH) under amethallothionein I promoter are used (Wanke, R., et al. PediatricNephrol (1991) 5:513-521). Genotype can be confirmed by genomic PCR withbovine GH specific primers (Wanke, R., et al. Pediatric Nephrol (1991)5:513-521). Glomeruli can be isolated after pooling kidneys from two ormore animals. For the animal model, accelerated nephrotoxic serumnephritis (NTX) is induced in 4 to 6 week old females as previouslyreported (Schadde, E., et al. Nephrol Dial Transplant (2000)15:1046-1053; Neugarten, J., et al. J. Am Soc Nephrol (1995)5:1903-1909). Five days after preimmunization with rabbit IgG, 400 μg ofa protein A purified IgG fraction of a nephrotoxic rabbit anti-murineGBM antiserum is intravenously injected, while controls receive carrieronly. Mice in each group are sacrificed after 0, 2, and 7 days and apooled glomerular fraction is obtained from each group for expressionanalysis. Albuminuria is determined using a commercially available mousealbumin specific ELISA system (Exocell, Philadelphia, PE).

Measuring Levels of ILK from Podocytes

To assess the efficacy of a candidate aminopyrazole ILK inhibiting agentin vivo, the following podocyte extraction method may be used. Singlecell RT-PCR is performed as described in Schroppel, B., et al. KidneyInt (1998) 53:119-124. Freshly dissected glomeruli from CD-1 mice aretransferred to a patch clamp apparatus. Single podocytes are selectivelyharvested by aspiration of the cells into a micropipette. Reversetranscribed and RT-PCR is performed essentially as described above, butusing 50 instead of 30 cycles. Perfusion medium aspirated next to aglomerulus is processed in parallel and serves as negative control.Single cell ILK RT-PCR product identity is verified by restrictiondigest. Single podocyte RNA is quantified using published real-timeRT-PCR technology (Heid, C. A., et al. Genome Res (1996) 6:986-994). Fordetermination of ILK copy number per single podocyte cDNA, a standardcurve of serial dilutions of ILK plasmid cDNA with known copy numbers isemployed. ILK copies per podocyte cDNA are calculated using the Ct valueminus the dilution factor and the standard curve (y=−1.6227 Ln(x)+39with R2=0.9935) generated from duplicate amplification reactions of logfold dilutions between 100,000 and 10 ILK plasmid copies.

In Vitro Podocytes Model:

As an in vitro model system, conditionally immortalized podocytes areused (Mundel, P., et al. Exp Cell Res (1997) 236:248-258). Cells arepropagated under permissive conditions at 33° C. with RPMI 1640 medium(Life Technologies) supplemented with 10% FCS (Bio Whittaker, Verviers,Belgium), 100 U/ml penicillin, 100 mg/ml streptomycin and 10 U/ml mouserecombinant interferon-g (Sigma). To induce differentiation, podocytesare maintained on type I-collagen (Biochrom, Berlin, FRG) coated surfaceat 37° C. without interferon-g (non-permissive conditions) for at least8 days. Cells at passage 12-24 were used. Mouse mesangial cells wereemployed in control experiments. 90-Day-old mice with severe albuminuriaare employed. Wildtype littermates serve as controls. Six to eightanimals in each group are analyzed.

GROUP ANIMAL TYPE TREATMENT Negative control Wildtype litter mates, weekCarrier only group: 6-12 of disease progression Positive controlGH-transgenic mice, week Carrier only group 6-12 of disease progressionTest animals GH-TX mice Various doses of ILK inhibitor weeks 6-12 Testanimals GH-TX mice Various doses of ILK inhibitor for full 12 weeks.

Compounds of the invention are administered orally, intraperitoneally orby subcutaneous infusion pump, in daily doses ranging from 0.01-200mg/kg. Vehicle (carrier) controls are administered in equivalent volumesby the same routes.

Experimental readouts included albuminuria, serum urea, histology andgene expression profiles.

Negative control mice demonstrate no significant changes in experimentalreadouts. The positive control group demonstrate significant changesassociated with progressive renal glomerulosclerosis in histology andbiochemical readouts. In the experimental GH-TX groups treated withvarious doses of aminopyrazole ILK inhibitor, decreases in measuredparameters of progressive renal glomerulosclerosis are demonstratedcompared to the positive control group, indicating that administrationof aminopyrazole ILK inhibitors results in therapeutic benefit in thismodel of progressive renal disease.

Example 107 Adriamycin-Induced Proteinuria

This model, which results in focal glomerular sclerosis (FGS), is welldescribed in Wang, Y., et al. Kidney Int (2000) 58:1797-1804. Groups ofBALB/c mice are injected intravenously on day 0 with a single dose ofAdriamycin (ADR, doxorubicin hydrochloride, Pharmacia & Upjohn) at 10-11mg/kg, or vehicle control. Six to eight animals in each group areanalyzed.

GROUP TREATMENT Negative control group Intravenous carrier on day 0,vehicle daily from day 0 Positive control group intravenous ADR on day0, vehicle daily from day 0 Test group Intravenous ADR on day 0, variousdoses of ILK inhibitor from day 0

Compounds of the invention are administered orally, intraperitoneally orby subcutaneous infusion pump, in daily doses ranging from 0.01-200mg/kg, beginning on day 0. Vehicle (carrier) controls are administeredin equivalent volumes by the same routes.

Experimental readouts include weekly body weight, urine volume, urinaryprotein, serum creatinine and albumin, and terminal histopathology.Negative control mice demonstrate no significant changes in experimentalreadouts. The positive control group demonstrate significant changesassociated with rapid progressive renal disease (FGS) using experimentalreadouts, namely proteinuria, hypoalbuminemia, hypercreatininemia, andprogressive renal injury by histology. In the experimental groupstreated with various doses of aminopyrazole ILK inhibitor, decreases inmeasured parameters of progressive renal disease are demonstratedcompared to the positive control group, indicating that administrationof aminopyrazole ILK inhibitors results in therapeutic benefit in thismodel of acute progressive focal glomerular sclerosis.

Example 108 Murine Unilateral Ureteral Obstruction

This model results in epithelial-mesenchymal transdifferentiation inrenal fibrosis and is described in Vielhauer V., et al. J. Am SoxNephrol (2001) 12: 1173-1187. Briefly, female inbred C57BL/6 miceweighing ca. 20-26 g are obtained and kept under a ca. 12-h light/darkcycle. Food and water are available ad libitum. Under generalanesthesia, unilateral ureteral ligation resulting in UUO is performedby ligating the left distal ureter with a 2/0 Mersilene suture thorugh alow midline abdominal incision. Unobstructed contralateral kidneys serveas controls.

GROUP (8-10 mice) PRE-TREATMENT TREATMENT Negative control Sham operatedmice Receive carrier only for group ten days Positive control Mice withone Receive carrier only for group obstructed kidney ten days Test groupMice with one Receive various doses of obstructed kidney ILK inhibitorfor ten days

Compounds of the invention are administered orally, intraperitoneally orby subcutaneous infusion pump, in daily doses ranging from 0.01-200mg/kg. Vehicle (carrier) controls are administered in equivalent volumesby the same routes.

Experimental readouts included histological fibrosis scores, serum urea,collagen levels and ILK mRNA expression. Analysis of ILK mRNA levels arealso performed in infiltrating cells (macrophages and T-cells) aftercell sorting in renal fibrosis in the UUO model. Negative control (shamoperated) mice demonstrate no significant changes in experimentalreadouts. The UUO control group demonstrate significant changesassociated with renal fibrosis in the ligated kidney using experimentalreadouts. Also observed in these animals is an increase in ILK mRNAinduction. In the experimental groups treated with various doses ofaminopyrazole ILK inhibitor, the non-ligated kidneys are used asinternal controls, and the non-ligated kidneys demonstrate nosignificant changes associated with renal tubulo-interstitial fibrosisusing experimental readouts, however the damaged kidneys demonstratedecreases in measured parameters of renal fibrosis compared to the UUOcontrol group. This result indicates that administration of compounds ofthe invention results in therapeutic benefit in this model of renaltubulo-interstitial fibrosis.

Example 109 Treatment of AMD using an ILK Inhibitor as an Adjunct toVisudyne™ Therapy

Therapeutic effect of a compound of the invention in AMD is evaluatedusing visual acuity as the primary clinical outcome. Patients withsubforveal CNV lesions caused by AMD are examined for the presence oflesions that meet the inclusion criteria. The inclusion criteria aredefined as the presence of lesions measuring 5400 μm or less in greatestlinear dimension with evidence of classic CNV and best-corrected visualacuity of approximately 20/40 to 20/200 based on fluoresceinangiographic and visual acuity examination. Those determined asqualified for the treatment of AMD are randomly assigned to 4 groups.Group A, B, and C are treated with standard Visudyne™ therapy with anadjunct therapy using an ILK inhibitor. Patients of Group D are treatedwith standard Visudyne™ therapy in combination with a placebo of the ILKinhibitor.

For standard Visudyne™ therapy, patients are administered with 30 ml ofVisudyne™ (0.15 mg per kilogram of body weight). The administration isby intravenous infusion over a period of 10 minutes. Fifteen minutesafter the end of the infusion, the laser light is applied for 83 secondsto the CNV lesion through a fundus contact lens of known magnificationto result in a light exposure of 50 J/cm². A circular spot ofapproximately 6000 microns encompassing the area of the lesion isexposed to the laser light.

For the adjunct therapy, patients of groups A, B, and C receive a dailyoral administration of a compound of the invention at the dose of 5, 10,20 mg per kilogram body weight, respectively. The adjunct treatmentcommences three days after the patient receiving the standard Visudyne™therapy and continues for a period of one month.

As follow-up, patients are examined every three months. At eachregularly scheduled follow-up visit, best-corrected visual acuitymeasurement, contrast threshold measurement, ophthalmoscopicexamination, stereoscopic fundus photography, and fluoresceinangiography are performed.

Example 110 Treatment of Diabetic Retinopathy using an ILK Inhibitor

Therapeutic effect of a compound of the invention in proliferativediabetic retinopathy is evaluated using visual acuity as the primaryclinical outcome. Patients with proliferative diabetic retinopathy andvisual acuity of 20/100 or better in each eye are included in theclinical evaluation. Patients are randomly assigned to 3 treatmentgroups and 1 placebo group. Group A, B, and C are treated with dailyoral administration of a compound of the invention at the dose of 5, 10,20 mg per kilogram body weight. Patients of Group D receive placebo. Thetreatment expands a period of 24 months.

As follow-up, patents are examined every 4 months. At each regularlyscheduled follow-up visit, best-corrected visual acuity measurement,contrast threshold measurement, indirect ophthalmoscopic examination,stereoscopic fundus photography, fluorescein angiography, and slit-lampexamination using 78- or 90-diopter lens are performed.

Example 111 Evaluation of ILK Expression in Ocular Vascular Tissue

This example indicates the relevance of ILK as a therapeutic target fordiseases with underling pathology of ocular neovascularization.

Post mortem baboon eye samples were subjected to immunohistologicalanalysis for the expression of ILK in ocular vasculature. Freshlyobtained tissues were snap-frozen by immersing into a Dewar of liquidnitrogen. Cross sections of 5-10 microns were prepared and fixed in coldacetone (−20 C). Immunohistology was performed using a rabbit anti-ILKantibody (Upstate Biotechnology Institute, NY. Cat. #06-550) and ZymedHistostatin™ Plus kit (Zymed, Cat. #85-9743).

Abundant expression of ILK was detected in choroidal and retinalendothelium in post mortem baboon eye samples. Under similar condition,no significant level of ILK expression was detected in retinal pigmentedepithelial cells. In addition, no significant expression of ILK inneurons and photoreceptors was observed.

Example 112 Treatment of Corneal Neovascularization with an ILKInhibitor using a Mouse Model

The following model provides a quantifiable in vivo assay that can beused to evaluate anti-angiogenic activity of a compound of theinvention. Corneal neovascularization is induced by a procedure known assilver nitrate cauterization. The procedure involves topicalapplications of silver nitrate onto the cornea by gently touchingconjunctiva/limbus for one second followed by touching the centralcornea of an anesthetized mouse for 8 seconds with a silver nitrateapplicator (Graham-Field, NY, Item #1590, 75% silver nitrate, 25%potassium nitrate). Immediately after, the eye is rinsed with 10 ml ofsaline followed by topical application of Gentak Ophthalmic Ointment(0.3%, Gentamicin sulfate) on the eye to prevent bacterial infections.

Corneal neovascularization is recorded and evaluated by examining andphotographing the cornea daily using a stereo dissecting microscopeconnected to a color video camera and a computer. Angiogenesis isevaluated based on new blood vessel growth within previous avascularcornea using a scoring system (score of 0-4) that rates from noneovascularization to very severe neovascularization in cornea. Inaddition, upon completion of the experiment (day 5-7), cornealneovascularization is quantified using computer-assisted image analysis(Image Pro Plus, Media Cybernetics, ML) of dye-stained blood vessels inpost mortem whole corneal mounts. Corneal vasculature is stained by IVinjection of high molecular weight FITC-dextran into anesthetized micebefore euthanasia.

Animals receive daily intra-peritoneal administration of a compound ofthe invention at the dose of 5, 25 or 50 mg/kg commencing on day-2 afterthe silver nitrate cauterization procedure until 24 h before the endingof the experiment. Corneal neovascularization of ILK inhibitor-treatedanimals is compared with that of vehicle-treated animals.

Example 113 Treatment of Choroidal Neovascularization with an ILKInhibitor Using a Monkey Model of CNV

The following model provides an in vivo assay that can be used toevaluate therapeutic potential of a compound of the invention for thetreatment of CNV. CNV is induced by argon green laser burns that areplaced in the maculae of cynomolgus monkeys using a modification ofRyan's model. The laser burn with size of 50 □m in diameter is inducedby exposure to 350-450 mW laser light at 514 nm for 0.1 second using anargon laser (Coherent Argon Dye Laser #920, Coherent Medical Laser, PoloAlto, Calif.).

CNV is monitored by weekly examination with fundus photography andfluorescein angiography. At the termination of the experiment (2-3months after the induction of CNV), eyes are enucleated under deepanesthesia and fixed in modified Kanovsky fixative. Bisection isperformed 20 minutes after fixation. Tissues are then embedded andsections are generated for histological and immunohistological analysisusing antibodies against vasculature-specific markers including CD-31and VE-Cadherin. The extent of neovascularization is quantified using acomputer-assisted image analysis system with Image Pro Plus (MediaCybernetics, ML).

Animals receive daily oral administration of a compound of the inventionat the dose of 10, 50 or 100 mg/kg for commencing after the onset of CNV(2-3 weeks after the laser treatment). As control, a group of monkeysreceive daily oral treatment with vehicle only. CNV in ILKinhibitor-treated animals is compared with that of vehicle-treatedanimals for angiographic and immunohistological evidence of CNV.

Example 114 Treatment of Retinal Neovascularization with an ILKInhibitor Using a Mouse Model of Ischmia-lnduced Retinopathy

The following model provides an in vivo assay that can be used toevaluate therapeutic potential of a compound of the invention for thetreatment of retinopathy. This is a mouse model of retinopathy ofprematurity. Retinopathy in mice is induced by using dams and neonatalmice. Mice are exposed with their nursing dams to 75% oxygen/25%nitrogen from postnatal day 7 to day 12, then put back to room air. Atday 17, all pups are weighed, euthanised, and perfused with 1 mlfixative (4% paraformaldhyde/8% sucrose/sodium phosphate buffer, pH 7.2)through the left ventricle of heart. Eyes are enucleated and placed infixative. The fixed tissues are paraffin-embedded and 4-μm sections arecut. Immunohistology procedure is performed to evaluate extent ofretinal neovascularization using antibodies against endothelium-specificmarkers including CD-31 and VE-cadherin. The vascular specific stainingis quantified using the computer-assisted image analysis method (ImagePro Plus, Media Cybernetics, ML).

The compound of the invention at the dose of 5, 25 or 50 mg/kg isadministered daily through intra-peritoneal injection from day 12through day 16. The control group receives daily injection of vehicle.The inhibitory effect of the ILK inhibitor on retinal neovascularizationis determined by comparing the extent of vascular staining in micetreated with the compound of the invention and those treated withvehicle only.

Example 115 B16 Murine Lung Metastasis Model

This model involves the injection of 200,000 tumour cells into the tailvein of mice. The tumour cells will seed into the lungs and form smalltumours there. Intraperitoneal or intravenous injection, or oral gavagetreatments will be commence either the day before after injection of thecells and will be performed daily. There will be 10 animals for eachtreatment group. The treatments will be administered at well tolerateddoses and no deleterious side effects are expected. Due to the variationof cell viability, n=4 control mice will be euthanized to monitor thecell number and growth in the lungs progressively throughout the study.Pilot studies have shown that monitoring should begin at 7 days andcontinue approximately on day 10, day 14 and until day 17 if necessary.When the tumour nodules in these control mice average 100 nodules peranimal, mice will be anesthetized by a Ketamine/Xylazine injection givenintraperitoneally and the entire study group of animals will besacrificed and necropsy performed. The lungs containing the metastatictumours will be excised, weighed and fixed in formalin. The tumours arevisibly distinct from normal lung tissue (change in pigment) and thenumber of metastasis or tumours that have formed in the lungs can becounted using a dissecting microscope. Cells are classified by sizebeing identified as small <0.2 mm, medium 0.2-0.5 mm or large >0.5 mm.Survival without treatment in this model has been established to be 28days after the initial injection of the tumour cells. Overall health ofthe mice is observed and weights are taken twice per week.

Progression of the cell burden within the lungs will be monitored bysacrificing non-treated animals at various time points. When the tumournodule count averages 100 nodules per animal the study will be concludedand all animals sacrificed. This is expected to be around day 14 to day17.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of formula (Ia):

wherein: n is 0; R³ is —NH₂; R⁴ is —N(R⁷)₂, —NHR⁷; —NHC(O)R⁶ or—N(R⁷)C(O)R⁶; R⁵ is aryl optionally substituted with one or moresubstituents selected from the group consisting of alkyl, halo, nitro,cyano, haloalkyl, haloalkoxy, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2), —S(O)_(t)—R⁸—OR⁶,—S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶, —R⁸—C(O)OR⁶, —C(O)N(R⁶)₂,—N(R⁷)₂, —NH₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶; or R⁵ is heterocyclyloptionally substituted with one or more substituents selected from thegroup consisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy,aryl, heterocyclyl, heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶(where m is 1 to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2),—S(O)_(t)—R⁸—OR⁶, —S(O)_(t)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶,—R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —NH₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;each R⁶ is independently hydrogen, alkyl, or aralkyl; each R⁷ isindependently alkyl, or aralkyl; each R⁸ is a straight or branchedalkylene chain; and each R⁹ is hydrogen or alkyl; as a singlestereoisomer, a mixture of stereoisomers, a solvate or a polymorph; or apharmaceutically acceptable salt thereof.
 2. The pharmaceuticalcomposition of claim 1 wherein: n is 0; R⁵ is aryl optionallysubstituted with one or more substituents selected from the groupconsisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy, aryl,heterocyclyl, heterocyclylalkyl, —OR⁶, —R⁸—OR⁶, —R⁸—[O—R⁸]_(m)—OR⁶(where m is 1 to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where t is 0 to 2),—S(O)_(t)—R⁸—OR⁶, —S(O)—N(R⁶)_(a), —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶,—R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —NH₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;each R⁶ is independently hydrogen, alkyl, or aralkyl; each R⁷ isindependently alkyl, or aralkyl; each R⁸ is a straight or branchedalkylene chain; and each R⁹ is hydrogen or alkyl.
 3. The pharmaceuticalcomposition of claim 2 wherein: n is 0; R⁴ is —NHR⁷ or —N(R⁷)₂; R⁵ isaryl optionally substituted with one or more substituents selected fromthe group consisting of alkyl, halo, nitro, cyano, haloalkyl,haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR⁶, —R⁸—OR⁶,—R⁸—[O—R⁸]_(m)—OR⁶ (where m is 1 to 4), —S(O)₂OH, —S(O)_(t)R⁷ (where tis 0 to 2), —S(O)_(t)—R⁸—OR⁶, —S(O)—N(R⁶)₂, —R⁸—P(O)(OR⁹)₂, —C(O)OR⁶,—R⁸—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁷)₂, —NH₂, —R⁸—N(R⁷)₂, and —N(R⁹)C(O)R⁶;each R⁶ is independently hydrogen, alkyl, or aralkyl; each R⁷ isindependently alkyl, or aralkyl; each R⁸ is a straight or branchedalkylene chain; and each R⁹ is hydrogen or alkyl.
 4. The pharmaceuticalcomposition of claim 3 wherein: n is 0; R⁴ is —NHR⁷ or —N(R⁷)₂; R⁵ isaryl optionally substituted with one or more substituents selected fromthe group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, andaralkyl, each R⁷ is independently alkyl, or aralkyl; each R⁸ is astraight or branched alkylene chain; and each R⁹ is hydrogen or alkyl.5. The pharmaceutical composition of claim 4 wherein: n is 0; R⁴ is—N(R⁷)₂; R⁵ is aryl optionally substituted with one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl,haloalkoxy, aryl and aralkyl; and each R⁷ is alkyl.
 6. Thepharmaceutical composition of claim 5 wherein: n is 0: R⁴ is —N(R⁷)₂; R⁵is phenyl optionally substituted with one or more substituents selectedfrom the group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl,and aralkyl optionally substituted by —N(R⁷)₂; and each R⁷ is alkyl. 7.A pharmaceutical composition comprising: a pharmaceutically acceptableexcipient and N-ethyl-4-(phenylhydrazono)-4H-pyrazole-3,5-diamine.